80 results on '"Prabir Ray"'
Search Results
2. Factor H preserves alternative complement function during ARDS, linked to improved survival
- Author
-
William Bain, Mohammadreza Tabary, Sara R. Moore, Xiaojing An, Georgios D. Kitsios, Bryan J. McVerry, Prabir Ray, Anuradha Ray, Rama K. Mallampalli, Viviana P. Ferreira, Janet S. Lee, and S. Mehdi Nouraie
- Subjects
Medicine - Abstract
Background Effective regulation of complement activation may be crucial to preserving complement function during acute respiratory distress syndrome (ARDS). Factor H is the primary negative regulator of the alternative pathway of complement. We hypothesised that preserved factor H levels are associated with decreased complement activation and reduced mortality during ARDS. Methods Total alternative pathway function was measured by serum haemolytic assay (AH50) using available samples from the ARDSnet Lisofylline and Respiratory Management of Acute Lung Injury (LARMA) trial (n=218). Factor B and factor H levels were quantified using ELISA using samples from the ARDSnet LARMA and Statins for Acutely Injured Lungs from Sepsis (SAILS) (n=224) trials. Meta-analyses included previously quantified AH50, factor B and factor H values from an observational registry (Acute Lung Injury Registry and Biospecimen Repository (ALIR)). Complement C3, and complement activation products C3a and Ba plasma levels were measured in SAILS. Results AH50 greater than the median was associated with reduced mortality in meta-analysis of LARMA and ALIR (hazard ratio (HR) 0.66, 95% CI 0.45–0.96). In contrast, patients in the lowest AH50 quartile demonstrated relative deficiency of both factor B and factor H. Relative deficiency of factor B (HR 1.99, 95% CI 1.44–2.75) or factor H (HR 1.52, 95% CI 1.09–2.11) was associated with increased mortality in meta-analysis of LARMA, SAILS and ALIR. Relative factor H deficiency was associated with increased factor consumption, as evidenced by lower factor B and C3 levels and Ba:B and C3a:C3 ratios. Higher factor H levels associated with lower inflammatory markers. Conclusions Relative factor H deficiency, higher Ba:B and C3a:C3 ratios and lower factor B and C3 levels suggest a subset of ARDS with complement factor exhaustion, impaired alternative pathway function, and increased mortality, that may be amenable to therapeutic targeting.
- Published
- 2023
- Full Text
- View/download PDF
3. Full Spectrum of LPS Activation in Alveolar Macrophages of Healthy Volunteers by Whole Transcriptomic Profiling.
- Author
-
Miguel Pinilla-Vera, Zeyu Xiong, Yutong Zhao, Jing Zhao, Michael P Donahoe, Suchitra Barge, William T Horne, Jay K Kolls, Bryan J McVerry, Anastasiya Birukova, Robert M Tighe, W Michael Foster, John Hollingsworth, Anuradha Ray, Rama Mallampalli, Prabir Ray, and Janet S Lee
- Subjects
Medicine ,Science - Abstract
Despite recent advances in understanding macrophage activation, little is known regarding how human alveolar macrophages in health calibrate its transcriptional response to canonical TLR4 activation. In this study, we examined the full spectrum of LPS activation and determined whether the transcriptomic profile of human alveolar macrophages is distinguished by a TIR-domain-containing adapter-inducing interferon-β (TRIF)-dominant type I interferon signature. Bronchoalveolar lavage macrophages were obtained from healthy volunteers, stimulated in the presence or absence of ultrapure LPS in vitro, and whole transcriptomic profiling was performed by RNA sequencing (RNA-Seq). LPS induced a robust type I interferon transcriptional response and Ingenuity Pathway Analysis predicted interferon regulatory factor (IRF)7 as the top upstream regulator of 89 known gene targets. Ubiquitin-specific peptidase (USP)-18, a negative regulator of interferon α/β responses, was among the top up-regulated genes in addition to IL10 and USP41, a novel gene with no known biological function but with high sequence homology to USP18. We determined whether IRF-7 and USP-18 can influence downstream macrophage effector cytokine production such as IL-10. We show that IRF-7 siRNA knockdown enhanced LPS-induced IL-10 production in human monocyte-derived macrophages, and USP-18 overexpression attenuated LPS-induced production of IL-10 in RAW264.7 cells. Quantitative PCR confirmed upregulation of USP18, USP41, IL10, and IRF7. An independent cohort confirmed LPS induction of USP41 and IL10 genes. These results suggest that IRF-7 and predicted downstream target USP18, both elements of a type I interferon gene signature identified by RNA-Seq, may serve to fine-tune early cytokine response by calibrating IL-10 production in human alveolar macrophages.
- Published
- 2016
- Full Text
- View/download PDF
4. Rapid host defense against Aspergillus fumigatus involves alveolar macrophages with a predominance of alternatively activated phenotype.
- Author
-
Shikha Bhatia, Mingjian Fei, Manohar Yarlagadda, Zengbiao Qi, Shizuo Akira, Shinobu Saijo, Yoichiro Iwakura, Nico van Rooijen, Gregory A Gibson, Claudette M St Croix, Anuradha Ray, and Prabir Ray
- Subjects
Medicine ,Science - Abstract
The ubiquitous fungus Aspergillus fumigatus is associated with chronic diseases such as invasive pulmonary aspergillosis in immunosuppressed patients and allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis or severe asthma. Because of constant exposure to this fungus, it is critical for the host to exercise an immediate and decisive immune response to clear fungal spores to ward off disease. In this study, we observed that rapidly after infection by A. fumigatus, alveolar macrophages predominantly express Arginase 1 (Arg1), a key marker of alternatively activated macrophages (AAMs). The macrophages were also found to express Ym1 and CD206 that are also expressed by AAMs but not NOS2, which is expressed by classically activated macrophages. The expression of Arg1 was reduced in the absence of the known signaling axis, IL-4Rα/STAT6, for AAM development. While both Dectin-1 and TLR expressed on the cell surface have been shown to sense A. fumigatus, fungus-induced Arg1 expression in CD11c(+) alveolar macrophages was not dependent on either Dectin-1 or the adaptor MyD88 that mediates intracellular signaling by most TLRs. Alveolar macrophages from WT mice efficiently phagocytosed fungal conidia, but those from mice deficient in Dectin-1 showed impaired fungal uptake. Depletion of macrophages with clodronate-filled liposomes increased fungal burden in infected mice. Collectively, our studies suggest that alveolar macrophages, which predominantly acquire an AAM phenotype following A. fumigatus infection, have a protective role in defense against this fungus.
- Published
- 2011
- Full Text
- View/download PDF
5. Early life exposure to house dust mite allergen prevents experimental allergic asthma requiring mitochondrial H2O2
- Author
-
Huijuan Yuan, Sudipta Das, Anuradha Ray, Sanmei Hu, Seyed Mehdi Nouraie, Sagar Laxman Kale, Jie Chen, Prabir Ray, and Timothy B. Oriss
- Subjects
House dust mite ,Lung ,biology ,business.industry ,Immunology ,respiratory system ,medicine.disease ,biology.organism_classification ,medicine.disease_cause ,respiratory tract diseases ,Immune tolerance ,Ovalbumin ,Allergen ,medicine.anatomical_structure ,In vivo ,medicine ,biology.protein ,Immunology and Allergy ,Eosinophilia ,medicine.symptom ,business ,Asthma - Abstract
Immune tolerance to allergens in early-life decreases the risk for asthma in later life. Here we show establishment of stable airway tolerance to the allergen, house dust mite (HDM), by exposing newborn mice repeatedly to a low dose of the allergen. Lung dendritic cells (DCs) from tolerized mice induced a low Th2 response in vitro mirroring impact of tolerance in vivo. In line with our previous finding of increased mitochondrial H2O2 production from lung DCs of mice tolerized to ovalbumin, depletion of mitochondrial H2O2 in MCAT mice abrogated HDM-induced airway tolerance (Tol) with elevated Th2 effector response, airway eosinophilia, and increased airway hyperreactivity. WT-Tol mice displayed a decrease in total, cDC1 and cDC2 subsets in the lung as compared to that in naive mice. In contrast, the lungs of MCAT-Tol mice showed 3-fold higher numbers of cDCs including those of the subsets as compared to that in WT mice. Our study demonstrates an important role of mitochondrial H2O2 in constraining lung DC numbers towards establishment of early-life airway tolerance to allergens.
- Published
- 2022
6. COVID-19 versus Non–COVID-19 Acute Respiratory Distress Syndrome: Comparison of Demographics, Physiologic Parameters, Inflammatory Biomarkers, and Clinical Outcomes
- Author
-
Georgios D Kitsios, Dario A. A. Vignali, Feng Shan, Callie Drohan, N. Bensen, Haopu Yang, Rebecca S. DeSensi, William Bain, Barbara Methé, Yingze Zhang, Bryan J. McVerry, Tullia C. Bruno, Caleb Lampenfeld, Nameer Al-Yousif, Alison Morris, Tomeka Suber, Carly Cardello, Faraaz Ali Shah, Janet S. Lee, Brian R. Rosborough, Prabir Ray, Anthony R. Cillo, Creg J. Workman, Ashwin Somasundaram, Caitlin Schaefer, and Anuradha Ray
- Subjects
Pulmonary and Respiratory Medicine ,ARDS ,medicine.medical_specialty ,Critical Care ,medicine.medical_treatment ,Lung injury ,Pulmonary compliance ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,pneumonia ,030212 general & internal medicine ,Prospective cohort study ,Original Research ,Mechanical ventilation ,business.industry ,SARS-CoV-2 ,COVID-19 ,acute respiratory distress syndrome ,medicine.disease ,Pneumonia ,030228 respiratory system ,business ,Respiratory minute volume ,Cohort study - Abstract
Rationale: There is an urgent need for improved understanding of the mechanisms and clinical characteristics of acute respiratory distress syndrome (ARDS) due to coronavirus disease (COVID-19). Objectives: To compare key demographic and physiologic parameters, biomarkers, and clinical outcomes of COVID-19 ARDS and ARDS secondary to direct lung injury from other etiologies of pneumonia. Methods: We enrolled 27 patients with COVID-19 ARDS in a prospective, observational cohort study and compared them with a historical, pre–COVID-19 cohort of patients with viral ARDS (n = 14), bacterial ARDS (n = 21), and ARDS due to culture-negative pneumonia (n = 30). We recorded clinical demographics; measured respiratory mechanical parameters; collected serial peripheral blood specimens for measurement of plasma interleukin (IL)-6, IL-8, and IL-10; and followed patients prospectively for patient-centered outcomes. We conducted between-group comparisons with nonparametric tests and analyzed time-to-event outcomes with Kaplan-Meier and Cox proportional hazards models. Results: Patients with COVID-19 ARDS had higher body mass index and were more likely to be Black, or residents of skilled nursing facilities, compared with those with non–COVID-19 ARDS (P < 0.05). Patients with COVID-19 had lower delivered minute ventilation compared with bacterial and culture-negative ARDS (post hoc P < 0.01) but not compared with viral ARDS. We found no differences in static compliance, hypoxemic indices, or carbon dioxide clearance between groups. Patients with COVID-19 had lower IL-6 levels compared with bacterial and culture-negative ARDS at early time points after intubation but no differences in IL-6 levels compared with viral ARDS. Patients with COVID-19 had longer duration of mechanical ventilation but similar 60-day mortality in both unadjusted and adjusted analyses. Conclusions: COVID-19 ARDS bears several similarities to viral ARDS but demonstrates lower minute ventilation and lower systemic levels of IL-6 compared with bacterial and culture-negative ARDS. COVID-19 ARDS was associated with longer dependence on mechanical ventilation compared with non–COVID-19 ARDS. Such detectable differences of COVID-19 do not merit deviation from evidence-based management of ARDS but suggest priorities for clinical research to better characterize and treat this new clinical entity.
- Published
- 2021
7. Increased Alternative Complement Pathway Function and Improved Survival during Critical Illness
- Author
-
Sara R. Moore, Alison Morris, Bryan J. McVerry, Hui-Hua Li, Mehdi Nouraie, Mei Hulver, Rebecca S. DeSensi, Erin Papke, Yohei Doi, Georgios D Kitsios, Melissa Saul, William Bain, Rick van der Geest, Tolani F. Olonisakin, Prabir Ray, Rama K. Mallampalli, Viviana P. Ferreira, Yingze Zhang, Lina Ma, Brian Ahn, Sarah F. Rapport, Janet S. Lee, Hrishikesh S. Kulkarni, Zeyu Xiong, and Kaveh Moghbeli
- Subjects
Pulmonary and Respiratory Medicine ,business.industry ,fungi ,food and beverages ,Improved survival ,Inflammation ,Critical Care and Intensive Care Medicine ,Complement (complexity) ,03 medical and health sciences ,0302 clinical medicine ,030228 respiratory system ,Immunology ,Critical illness ,Alternative complement pathway ,Medicine ,030212 general & internal medicine ,medicine.symptom ,business ,Function (biology) - Abstract
Rationale: Complement is crucial for host defense but may also drive dysregulated inflammation. There is limited understanding of alternative complement function, which can amplify all complement a...
- Published
- 2020
8. Host-Response Subphenotypes Offer Prognostic Enrichment in Patients With or at Risk for Acute Respiratory Distress Syndrome*
- Author
-
Dimitris V. Manatakis, Georgios D Kitsios, Janet S. Lee, L. Yang, Mehdi Nouraie, John Evankovich, Nathaniel M. Weathington, Bill B. Chen, Daniel G. Dunlap, Rama K. Mallampalli, Bryan J. McVerry, Prabir Ray, Ian J. Barbash, Alison Morris, William Bain, Rebecca S. DeSensi, Yingze Zhang, Panayiotis V. Benos, Faraaz Ali Shah, and Sarah F. Rapport
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Host response ,Acute respiratory distress ,Critical Care and Intensive Care Medicine ,Plasma biomarkers ,Risk Assessment ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,In patient ,Prospective Studies ,Respiratory system ,Prospective cohort study ,Aged ,Inflammation ,Respiratory Distress Syndrome ,business.industry ,030208 emergency & critical care medicine ,Middle Aged ,Prognosis ,Phenotype ,030228 respiratory system ,Female ,Risk assessment ,business ,Biomarkers - Abstract
Classification of patients with acute respiratory distress syndrome into hyper- and hypoinflammatory subphenotypes using plasma biomarkers may facilitate more effective targeted therapy. We examined whether established subphenotypes are present not only in patients with acute respiratory distress syndrome but also in patients at risk for acute respiratory distress syndrome (ARFA) and then assessed the prognostic information of baseline subphenotyping on the evolution of host-response biomarkers and clinical outcomes.Prospective, observational cohort study.Medical ICU at a tertiary academic medical center.Mechanically ventilated patients with acute respiratory distress syndrome or ARFA.None.We performed longitudinal measurements of 10 plasma biomarkers of host injury and inflammation. We applied unsupervised latent class analysis methods utilizing baseline clinical and biomarker variables and demonstrated that two-class models (hyper- vs hypoinflammatory subphenotypes) offered improved fit compared with one-class models in both patients with acute respiratory distress syndrome and ARFA. Baseline assignment to the hyperinflammatory subphenotype (39/104 [38%] acute respiratory distress syndrome and 30/108 [28%] ARFA patients) was associated with higher severity of illness by Sequential Organ Failure Assessment scores and incidence of acute kidney injury in patients with acute respiratory distress syndrome, as well as higher 30-day mortality and longer duration of mechanical ventilation in ARFA patients (p0.0001). Hyperinflammatory patients exhibited persistent elevation of biomarkers of innate immunity for up to 2 weeks postintubation.Our results suggest that two distinct subphenotypes are present not only in patients with established acute respiratory distress syndrome but also in patients at risk for its development. Hyperinflammatory classification at baseline is associated with higher severity of illness, worse clinical outcomes, and trajectories of persistently elevated biomarkers of host injury and inflammation during acute critical illness compared with hypoinflammatory patients. Our findings provide strong rationale for examining treatment effect modifications by subphenotypes in randomized clinical trials to inform precision therapeutic approaches in critical care.
- Published
- 2019
9. Intractable Coronavirus Disease 2019 (COVID-19) and Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Replication in a Chimeric Antigen Receptor-Modified T-Cell Therapy Recipient: A Case Study
- Author
-
Matthew K Hensley, Jana L. Jacobs, Bernard J.C. Macatangay, Rahil Sethi, Ashwin Somasundaram, Feng Shan, Ghady Haidar, Brittany Staines, Anthony R. Cillo, Janet S. Lee, Linda J. Rennick, Amy Heaps, Anuradha Ray, Michele D. Sobolewski, William Bain, Barbara Methé, Tullia C. Bruno, Prabir Ray, Dario A. A. Vignali, John W. Mellors, William E. Schwarzmann, Georgios D Kitsios, W. Paul Duprex, Urvi M. Parikh, Creg J. Workman, Carly Cardello, Cynthia Klamar-Blain, Mounzer Agha, Sham Nambulli, Kevin D. McCormick, Mark S. Ladinsky, Pamela J. Bjorkman, and Alison Morris
- Subjects
0301 basic medicine ,Microbiology (medical) ,T cell ,viruses ,Cell- and Tissue-Based Therapy ,Virus Replication ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Immunity ,medicine ,Humans ,030212 general & internal medicine ,Coronavirus ,Receptors, Chimeric Antigen ,SARS-CoV-2 ,Transmission (medicine) ,business.industry ,Brief Report ,SARS-CoV-2 infectivity ,SARS-CoV-2 intrahost variation ,COVID-19 ,Virology ,Chimeric antigen receptor ,SARS-CoV-2 RNAemia ,AcademicSubjects/MED00290 ,030104 developmental biology ,medicine.anatomical_structure ,Infectious Diseases ,Viral replication ,Viral evolution ,SARS-CoV-2 immune responses ,business ,severe acute respiratory syndrome coronavirus 2 - Abstract
A chimeric antigen receptor-modified T-cell therapy recipient developed severe coronavirus disease 2019, intractable RNAemia, and viral replication lasting >2 months. Premortem endotracheal aspirate contained >2 × 1010 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA copies/mL and infectious virus. Deep sequencing revealed multiple sequence variants consistent with intrahost virus evolution. SARS-CoV-2 humoral and cell-mediated immunity were minimal. Prolonged transmission from immunosuppressed patients is possible.
- Published
- 2021
10. Platelets inhibit apoptotic lung epithelial cell death and protect mice against infection-induced lung injury
- Author
-
Hui-Hua Li, Mehdi Nouraie, Rama K. Mallampalli, Yanyan Qu, Mei Hulver, Joseph M. Pilewski, Tolani F. Olonisakin, Janet S. Lee, Claudette M. St. Croix, Zeyu Xiong, Anuradha Ray, Zhenyu Cheng, Robert M. Q. Shanks, Roy L. Silverstein, Minting Yu, William Bain, and Prabir Ray
- Subjects
Blood Platelets ,0301 basic medicine ,Programmed cell death ,Apoptosis ,Lung injury ,Thrombosis and Hemostasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,medicine ,Animals ,Secretion ,Platelet ,Lung ,Cell Death ,Apyrase ,business.industry ,Epithelial Cells ,Lung Injury ,Hematology ,respiratory system ,Thrombocytopenia ,respiratory tract diseases ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,business ,030215 immunology - Abstract
Thrombocytopenia is associated with worse outcomes in patients with acute respiratory distress syndrome, which is most commonly caused by infection and marked by alveolar–capillary barrier disruption. However, the mechanisms by which platelets protect the lung alveolar–capillary barrier during infectious injury remain unclear. We found that natively thrombocytopenic Mpl−/− mice deficient in the thrombopoietin receptor sustain severe lung injury marked by alveolar barrier disruption and hemorrhagic pneumonia with early mortality following acute intrapulmonary Pseudomonas aeruginosa (PA) infection; barrier disruption was attenuated by platelet reconstitution. Although PA infection was associated with a brisk neutrophil influx, depletion of airspace neutrophils failed to substantially mitigate PA-triggered alveolar barrier disruption in Mpl−/− mice. Rather, PA cell-free supernatant was sufficient to induce lung epithelial cell apoptosis in vitro and in vivo and alveolar barrier disruption in both platelet-depleted mice and Mpl−/− mice in vivo. Cell-free supernatant from PA with genetic deletion of the type 2 secretion system, but not the type 3 secretion system, mitigated lung epithelial cell death in vitro and lung injury in Mpl−/− mice. Moreover, platelet releasates reduced poly (ADP ribose) polymerase cleavage and lung injury in Mpl−/− mice, and boiling of platelet releasates, but not apyrase treatment, abrogated PA supernatant–induced lung epithelial cell cytotoxicity in vitro. These findings indicate that while neutrophil airspace influx does not potentiate infectious lung injury in the thrombocytopenic host, platelets and their factors protect against severe pulmonary complications from pathogen-secreted virulence factors that promote host cell death even in the absence of overt infection.
- Published
- 2019
11. Bifurcated monocyte states are predictive of mortality in severe COVID-19
- Author
-
Chang Liu, Lawrence C. Andrews, Caleb Lampenfeld, Dario A. A. Vignali, W. Paul Duprex, Alison Morris, Anuradha Ray, Sham Nambulli, Sheryl Kunning, Jishnu Das, Bryan J. McVerry, Georgios D Kitsios, Creg J. Workman, Janet S. Lee, Alok J Joglekar, Ashwin Somasundaram, Carly Cardello, Prabir Ray, Gaurav Deshmukh, Harinder Singh, Barbara Methé, Ayana T. Ruffin, Anthony R. Cillo, Stephanie Grebinowski, Tullia C. Bruno, Panayiotis V. Benos, Sayali Onkar, Yingze Zhang, and Feng Shan
- Subjects
ARDS ,business.industry ,Monocyte ,Disease ,medicine.disease ,Intensive care unit ,Article ,law.invention ,Proinflammatory cytokine ,Immune system ,medicine.anatomical_structure ,Interferon ,law ,Immunology ,Medicine ,CXCL10 ,business ,medicine.drug - Abstract
Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection presents with varied clinical manifestations1, ranging from mild symptoms to acute respiratory distress syndrome (ARDS) with high mortality2,3. Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in severe COVID-19. We performed high-dimensional cellular and molecular profiling of blood and respiratory samples from critically ill COVID-19 patients to define immune cell genomic states that are predictive of outcome in severe COVID-19 disease. Critically ill patients admitted to the intensive care unit (ICU) manifested increased frequencies of inflammatory monocytes and plasmablasts that were also associated with ARDS not due to COVID-19. Single-cell RNAseq (scRNAseq)-based deconvolution of genomic states of peripheral immune cells revealed distinct gene modules that were associated with COVID-19 outcome. Notably, monocytes exhibited bifurcated genomic states, with expression of a cytokine gene module exemplified by CCL4 (MIP-1β) associated with survival and an interferon signaling module associated with death. These gene modules were correlated with higher levels of MIP-1β and CXCL10 levels in plasma, respectively. Monocytes expressing genes reflective of these divergent modules were also detectable in endotracheal aspirates. Machine learning algorithms identified the distinctive monocyte modules as part of a multivariate peripheral immune system state that was predictive of COVID-19 mortality. Follow-up analysis of the monocyte modules on ICU day 5 was consistent with bifurcated states that correlated with distinct inflammatory cytokines. Our data suggests a pivotal role for monocytes and their specific inflammatory genomic states in contributing to mortality in life-threatening COVID-19 disease and may facilitate discovery of new diagnostics and therapeutics.
- Published
- 2021
12. Cardiolipin-mediated PPARγ S112 phosphorylation impairs IL-10 production and inflammation resolution during bacterial pneumonia
- Author
-
Aniruddha Mundhada, Saumya Johri, Shakti Sagar, Krishnendu Chakraborty, Mayank Garg, Prabir Ray, and Anurag Agrawal
- Subjects
Male ,0301 basic medicine ,PPARγ ,Cardiolipins ,medicine.medical_treatment ,SUMO protein ,Inflammation ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pneumonia, Bacterial ,Cardiolipin ,Animals ,Medicine ,pneumonia ,mitochondrial-DAMP ,Phosphorylation ,lcsh:QH301-705.5 ,lung inflammation resolution ,business.industry ,Macrophages ,Bacterial pneumonia ,medicine.disease ,Interleukin-10 ,Klebsiella Infections ,PPAR gamma ,Klebsiella pneumoniae ,Pneumonia ,Interleukin 10 ,RAW 264.7 Cells ,030104 developmental biology ,Cytokine ,chemistry ,lcsh:Biology (General) ,IL-10 ,Cancer research ,medicine.symptom ,business ,cardiolipin ,030217 neurology & neurosurgery - Abstract
SUMMARY Bacterial pneumonia is a global healthcare burden, and unwarranted inflammation is suggested as an important cause of mortality. Optimum levels of the anti-inflammatory cytokine IL-10 are essential to reduce inflammation and improve survival in pneumonia. Elevated levels of the mitochondrial-DAMP cardiolipin (CL), reported in tracheal aspirates of pneumonia patients, have been shown to block IL-10 production from lung MDSCs. Although CL-mediated K107 SUMOylation of PPARγ has been suggested to impair this IL-10 production, the mechanism remains elusive. We identify PIAS2 to be the specific E3-SUMOligase responsible for this SUMOylation. Moreover, we identify a concomitant CL-mediated PPARγ S112 phosphorylation, mediated by JNK-MAPK, to be essential for PIAS2 recruitment. Furthermore, using a clinically tested peptide inhibitor targeting JNK-MAPK, we blocked these post-translational modifications (PTMs) of PPARγ and rescued IL-10 expression, improving survival in murine pneumonia models. Thus, we explore the mechanism of mito-DAMP-mediated impaired lung inflammation resolution and propose a therapeutic strategy targeting PPARγ PTMs., Graphical Abstract, In Brief Garg et al. identify the role of post-translational modifications of PPARγ in causing cardiolipin-mediated IL-10 suppression from lung myeloid-derived suppressor cells, thus increasing pneumonia severity. They identify multiple targets to reverse this suppression and improve IL-10 expression and lung inflammation resolution in bacterial pneumonia.
- Published
- 2021
13. Interleukin-22 Inhibits Respiratory Syncytial Virus Production by Blocking Virus-Mediated Subversion of Cellular Autophagy
- Author
-
Misty Good, Jie Chen, Mark A. Ross, Sudipta Das, Jinming Zhao, Sanmei Hu, Anuradha Ray, John V. Williams, Michael M. Myerburg, Claudette M. St. Croix, Jay K. Kolls, Joseph M. Pilewski, Prabir Ray, and Sally E. Wenzel
- Subjects
0301 basic medicine ,medicine.medical_treatment ,viruses ,Immunology ,02 engineering and technology ,Virus ,Article ,Interleukin 22 ,03 medical and health sciences ,Virology ,medicine ,Respiratory system ,lcsh:Science ,Multidisciplinary ,Lung ,business.industry ,Respiratory disease ,virus diseases ,Cell Biology ,respiratory system ,021001 nanoscience & nanotechnology ,medicine.disease ,Pneumonia ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Bronchiolitis ,lcsh:Q ,0210 nano-technology ,business - Abstract
Summary Respiratory syncytial virus (RSV) infection can cause severe bronchiolitis in infants requiring hospitalization, whereas the elderly and immunocompromised are prone to RSV-induced pneumonia. RSV primarily infects lung epithelial cells. Given that no vaccine against RSV is currently available, we tested the ability of the epithelial-barrier protective cytokine interleukin-22 (IL-22) to control RSV production. When used in a therapeutic modality, IL-22 efficiently blunted RSV production from infected human airway and alveolar epithelial cells and IL-22 administration drastically reduced virus titer in the lungs of infected newborn mice. RSV infection resulted in increased expression of LC3B, a key component of the cellular autophagic machinery, and knockdown of LC3B ablated virus production. RSV subverted LC3B with evidence of co-localization and caused a significant reduction in autophagic flux, both reversed by IL-22 treatment. Our findings inform a previously unrecognized anti-viral effect of IL-22 that can be harnessed to prevent RSV-induced severe respiratory disease., Graphical Abstract, Highlights • RSV infection of lung epithelial cells subverts the cellular autophagic machinery • RSV infection inhibits autophagic flux in infected cells • IL-22 inhibits RSV production from human lung epithelial cells and in neonatal mice • IL-22 blocks RSV-LC3B co-localization and restores cellular autophagic flux, Immunology; Virology; Cell Biology
- Published
- 2020
14. Single Cell RNA Sequencing Identifies Type I Interferon Signaling and Reduced Suppressor of Cytokine Signaling 3 Expression in Monocytes of Acute Respiratory Distress Syndrome Patients
- Author
-
Jie Chen, Y. Jiang, Brian R. Rosborough, Anuradha Ray, Bryan J. McVerry, Wei Chen, Prabir Ray, and Georgios D Kitsios
- Subjects
medicine.anatomical_structure ,business.industry ,Interferon ,Cell ,medicine ,Cancer research ,RNA ,Acute respiratory distress ,SOCS3 ,business ,medicine.drug - Published
- 2020
15. Paired Multi-‘Omics Analysis of Peripheral Blood and Bronchoalveolar Lavage from Asthmatic Patients Identifies Distinct Immune Phenotypes
- Author
-
Kari C. Nadeau, Matthew J. Camiolo, Sally E. Wenzel, Wei Chen, T.B. Oriss, Prabir Ray, Xiaoying Zhou, and Anuradha Ray
- Subjects
Bronchoalveolar lavage ,Immune system ,medicine.diagnostic_test ,business.industry ,Immunology ,medicine ,Multi omics ,Asthmatic patient ,business ,Phenotype ,Peripheral blood - Published
- 2020
16. Increased Alternative Complement Pathway Function Improves Survival During Critical Illness
- Author
-
Mei Hulver, R. van der Geest, Zeyu Xiong, Rebecca S. DeSensi, B. Ahn, Sara R. Moore, Sarah F. Rapport, Seyed Mehdi Nouraie, Bryan J. McVerry, Alison Morris, Melissa Saul, William Bain, K. Moghbeli, Prabir Ray, Hui-Hua Li, Tolani F. Olonisakin, Yohei Doi, Rama K. Mallampalli, Viviana P. Ferreira, Georgios D Kitsios, Janet S. Lee, and Y. Zhang
- Subjects
business.industry ,Critical illness ,Alternative complement pathway ,Medicine ,business ,Bioinformatics ,Function (biology) - Published
- 2020
17. The Efficacy of CXCR3 and CCR5 Chemotaxis Blockade in Severe Asthma Is Limited by Lung Resident Memory T-Cells
- Author
-
Sagar Laxman Kale, Sally E. Wenzel, Anuradha Ray, Kathryn Scholl, Marc Gauthier, T.B. Oriss, and Prabir Ray
- Subjects
Lung ,medicine.anatomical_structure ,business.industry ,Severe asthma ,Immunology ,Medicine ,Chemotaxis ,business ,CXCR3 ,Blockade - Published
- 2020
18. High-dimensional profiling clusters asthma severity by lymphoid and non-lymphoid status
- Author
-
Sally E. Wenzel, Qi Yan, Florian Weisel, Matthew J. Camiolo, Xiaoying Zhou, Nadine M. Weisel, Timothy B. Oriss, Nima Aghaeepour, Kathryn Scholl, Jay K. Kolls, John B. Trudeau, Wei Chen, Kari C. Nadeau, William Horne, Anuradha Ray, Prabir Ray, and Michael C. Gorry
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,Proteomics ,Adaptive Immunity ,CD8-Positive T-Lymphocytes ,Severity of Illness Index ,Machine Learning ,0302 clinical medicine ,Interferon ,Adrenal Cortex Hormones ,Anti-Asthmatic Agents ,Biology (General) ,education.field_of_study ,Interleukin ,Acquired immune system ,Interleukin-10 ,CyTOF ,Bronchoalveolar Lavage Fluid ,medicine.drug ,Signal Transduction ,severe asthma ,QH301-705.5 ,Population ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Interferon-gamma ,Immune system ,medicine ,Humans ,Mass cytometry ,education ,Interleukin-7 receptor ,BAL ,Innate immune system ,Receptors, IgE ,Gene Expression Profiling ,Interleukin-7 ,Macrophages ,multi-omics ,Asthma ,Immunity, Innate ,030104 developmental biology ,Gene Expression Regulation ,Case-Control Studies ,Immunology ,immune ,RNA-seq ,Immunologic Memory ,030217 neurology & neurosurgery - Abstract
SUMMARY Clinical definitions of asthma fail to capture the heterogeneity of immune dysfunction in severe, treatment-refractory disease. Applying mass cytometry and machine learning to bronchoalveolar lavage (BAL) cells, we find that corticosteroid-resistant asthma patients cluster largely into two groups: one enriched in interleukin (IL)-4+ innate immune cells and another dominated by interferon (IFN)-γ+ T cells, including tissue-resident memory cells. In contrast, BAL cells of a healthier population are enriched in IL-10+ macrophages. To better understand cellular mediators of severe asthma, we developed the Immune Cell Linkage through Exploratory Matrices (ICLite) algorithm to perform deconvolution of bulk RNA sequencing of mixed-cell populations. Signatures of mitosis and IL-7 signaling in CD206−FcεRI+CD127+IL-4+ innate cells in one patient group, contrasting with adaptive immune response in T cells in the other, are preserved across technologies. Transcriptional signatures uncovered by ICLite identify T-cell-high and T-cell-poor severe asthma patients in an independent cohort, suggesting broad applicability of our findings., Graphical abstract, In brief Asthma is an immune-mediated heterogeneous disease. Current type-2 biomarkers provide limited understanding of underlying pathobiology or therapeutic guidance. Using a multi-omics approach, Camiolo et al. identify two clusters of severe asthma patients with similar type-2 biomarkers but with strikingly distinct immune profiles and associated biological pathways.
- Published
- 2020
19. Stressed erythrophagocytosis induces immunosuppression during sepsis through heme-mediated STAT1 dysregulation
- Author
-
Daniel B. Kim-Shapiro, Mark T. Gladwin, Shekina Gonzalez-Ferrer, David O. Osei-Hwedieh, Samuel L. Brashears, Hernán F. Peñaloza, Tolani F. Olonisakin, Michael A. Bachman, Yuting Xiong, Claudette M. St. Croix, Valerian E. Kagan, Tomeka Suber, Prabir Ray, Andreas Perlegas, Zeyu Xiong, Janet S. Lee, Yulia Y. Tyurina, Eldad A. Hod, Jesús Tejero, Wendy M. Mars, Rick van der Geest, Anuradha Ray, Rama K. Mallampalli, Daria Van Tyne, and Matthew R. Rosengart
- Subjects
0301 basic medicine ,Erythrocytes ,medicine.medical_treatment ,Heme ,Microbiology ,Sepsis ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Phagocytosis ,Immunity ,medicine ,Immune Tolerance ,Animals ,Humans ,STAT1 ,NRF1 ,Mice, Knockout ,Innate immune system ,biology ,Wild type ,Immunosuppression ,General Medicine ,medicine.disease ,030104 developmental biology ,STAT1 Transcription Factor ,chemistry ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,biology.protein ,Research Article - Abstract
Macrophages are main effectors of heme metabolism, increasing transiently in the liver during heightened disposal of damaged or senescent red blood cells (sRBC). Macrophages are also essential in defense against microbial threats, but pathologic states of heme excess may be immunosuppressive. Herein, we uncovered a mechanism whereby an acute rise in sRBC disposal by macrophages led to an immunosuppressive phenotype following intrapulmonary Klebsiella pneumoniae infection characterized by increased extrapulmonary bacterial proliferation and reduced survival from sepsis in mice. The impaired immunity to K. pneumoniae during heightened sRBC disposal was independent of iron acquisition by bacterial siderophores, as K. pneumoniae mutant lacking siderophore function recapitulated findings observed with wildtype strain. Rather, sRBC disposal induced a liver transcriptomic profile notable for suppression of Stat1 and interferon-related responses during K. pneumoniae sepsis. Excess heme handling by macrophages recapitulated STAT1 suppression during infection that required synergistic NRF1 and NRF2 activation but was independent of heme oxygenase-1 induction. Whereas iron was dispensable, the porphyrin moiety of heme was sufficient to mediate suppression of STAT1-dependent responses in human and mouse macrophages and promoted liver dissemination of K. pneumoniae in vivo. Thus, cellular heme metabolism dysfunction negatively regulates the STAT1 pathway with implications in severe infection.
- Published
- 2020
20. Dual role for CXCR3 and CCR5 in asthmatic type 1 inflammation
- Author
-
Sally E. Wenzel, Marc Gauthier, Huijuan Yuan, Sudipta Das, Sagar Laxman Kale, Matthew J. Camiolo, Timothy B. Oriss, Sanmei Hu, Jie Chen, Anuradha Ray, Prabir Ray, and Kathryn Scholl
- Subjects
Adult ,Male ,Receptors, CXCR3 ,Receptors, CCR5 ,Immunology ,Bronchi ,Respiratory Mucosa ,CCR5 receptor antagonist ,CXCR3 ,Severity of Illness Index ,Article ,CCL5 ,Maraviroc ,Interferon-gamma ,Young Adult ,Chemokine receptor ,chemistry.chemical_compound ,medicine ,Animals ,Humans ,Immunology and Allergy ,CXCL10 ,Inflammation ,Mice, Knockout ,medicine.diagnostic_test ,business.industry ,Airway Resistance ,Middle Aged ,Asthma ,respiratory tract diseases ,Mice, Inbred C57BL ,Bronchoalveolar lavage ,chemistry ,CCR5 Receptor Antagonists ,CXCL9 ,Female ,business ,Bronchoalveolar Lavage Fluid - Abstract
BACKGROUND: Many severe asthma (SA) patients fail to respond to Type 2 inflammation targeted therapies. We previously identified a cohort of SA subjects expressing Type 1 inflammation manifesting with IFN-γ expression with variable Type 2 responses. OBJECTIVE: We investigated the role of the chemotactic receptors CXCR3 and CCR5 in establishing Type 1 inflammation in SA. METHODS: Bronchoalveolar lavage microarray data from the Severe Asthma Research Program (SARP I/II) were analyzed for pathway expression and paired with clinical parameters. Wild Type, Cxcr3(−/−) and Ccr5(−/−) mice were exposed to a Type 1(High) SA model with analysis of whole lung gene expression and histology. Wild type and Cxcr3(−/−) mice were treated with an FDA-approved CCR5 inhibitor (maraviroc) with assessment of airway resistance, inflammatory cell recruitment by flow cytometry, whole lung gene expression and histology. RESULTS: A cohort of subjects with increased IFN-γ expression showed higher asthma severity. IFN-γ expression correlated with CXCR3 and CCR5 expression but in Cxcr3(−/−) and Ccr5(−/−) mice Type 1 inflammation was preserved in a murine SA model, most likely due to compensation by the other pathway. Incorporation of maraviroc in the experimental model blunted airway hyperreactivity, despite only mild effects on lung inflammation. CONCLUSIONS: IFNG expression in asthmatic airways was strongly correlated with expression of both the chemokine receptors CXCR3 and CCR5. While these pathways provide redundancy for establishing Type 1 lung inflammation, inhibition of the CCL5/CCR5 pathway with maraviroc provided unique benefits in reducing airway hyperreactivity. Targeting this pathway may be a novel approach for improving lung function in Type 1(high) asthmatic individuals. CLINICAL IMPLICATIONS: In Type 1 high asthma, CCR5 and CXCR3 provide redundant pathways for lung inflammation, but CCR5 inhibition provides a potential novel target for reducing airway hyperreactivity.
- Published
- 2022
21. Single cell RNA sequencing identifies an early monocyte gene signature in acute respiratory distress syndrome
- Author
-
Wei Chen, Anuradha Ray, Yale Jiang, Bryan J. McVerry, Rama K. Mallampalli, Jie Chen, Prabir Ray, Janet S. Lee, Brian R. Rosborough, Georgios D Kitsios, and Sudipta Das
- Subjects
0301 basic medicine ,ARDS ,Neutrophils ,Monocytes ,Proinflammatory cytokine ,Pathogenesis ,Sepsis ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Medicine ,Humans ,Efferocytosis ,Inflammation ,Respiratory Distress Syndrome ,business.industry ,Sequence Analysis, RNA ,Monocyte ,General Medicine ,Pneumonia ,Gene signature ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Single-Cell Analysis ,business ,Biomarkers ,Signal Transduction ,Research Article - Abstract
Acute respiratory distress syndrome (ARDS) results from overwhelming pulmonary inflammation. Prior bulk RNA sequencing provided limited insights into ARDS pathogenesis. We used single cell RNA sequencing to probe ARDS at a higher resolution. PBMCs of patients with pneumonia and sepsis with early ARDS were compared with those of sepsis patients who did not develop ARDS. Monocyte clusters from ARDS patients revealed multiple distinguishing characteristics in comparison with monocytes from patients without ARDS, including downregulation of SOCS3 expression, accompanied by a proinflammatory signature with upregulation of multiple type I IFN–induced genes, especially in CD16(+) cells. To generate an ARDS risk score, we identified upregulation of 29 genes in the monocytes of these patients, and 17 showed a similar profile in cells of patients in independent cohorts. Monocytes had increased expression of RAB11A, known to inhibit neutrophil efferocytosis; ATP2B1, a calcium pump that exports Ca(2+) implicated in endothelial barrier disruption; and SPARC, associated with processing of procollagen to collagen. These data show that monocytes of ARDS patients upregulate expression of genes not just restricted to those associated with inflammation. Together, our findings identify molecules that are likely involved in ARDS pathogenesis that may inform biomarker and therapeutic development.
- Published
- 2019
22. Single Cell RNA Sequencing Identifies an Acute Respiratory Distress Syndrome Monocyte Response
- Author
-
Bryan J. McVerry, Brian R. Rosborough, Sarah F. Rapport, Anuradha Ray, Yale Jiang, Prabir Ray, and Wei Chen
- Subjects
medicine.anatomical_structure ,business.industry ,Monocyte ,Cell ,Immunology ,Medicine ,RNA ,Acute respiratory distress ,business - Published
- 2019
23. Platelets Limit Apoptotic Lung Epithelial Cell Death and Protect Mice Against Infection-Induced Lung Injury
- Author
-
Joseph M. Pilewski, Mei Hulver, Janet S. Lee, Zeyu Xiong, Zhenyu Cheng, Yanyan Qu, C. St. Croix, Roy L. Silverstein, Prabir Ray, Seyed Mehdi Nouraie, Minting Yu, Hui-Hua Li, Rama K. Mallampalli, Tolani F. Olonisakin, William Bain, Anuradha Ray, and Robert M. Q. Shanks
- Subjects
medicine.anatomical_structure ,Lung ,business.industry ,Infection induced ,Apoptosis ,Cancer research ,Medicine ,Platelet ,Lung injury ,business ,Epithelium - Published
- 2019
24. Mitochondrial H2O2 in Lung Antigen-Presenting Cells Blocks NF-κB Activation to Prevent Unwarranted Immune Activation
- Author
-
Christina Morse, Rachael Huff, Christelle K. Kamga, Catherine Corey, Rachel Hannum, Sruti Shiva, Timothy B. Oriss, Kelly M. Quesnelle, Claudette M. St. Croix, Krishnendu Chakraborty, Prabir Ray, Anuradha Ray, Sudipta Das, Mahesh Raundhal, Simon C. Watkins, and Anupriya Khare
- Subjects
0301 basic medicine ,T-Lymphocytes ,Antigen-Presenting Cells ,Peroxisome proliferator-activated receptor ,Inflammation ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Immune tolerance ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,Immune Tolerance ,medicine ,Animals ,Promoter Regions, Genetic ,Antigen-presenting cell ,Lung ,lcsh:QH301-705.5 ,Cell Proliferation ,chemistry.chemical_classification ,Fatty Acids ,NF-kappa B ,Dendritic Cells ,Hydrogen Peroxide ,CD11c Antigen ,Mitochondria ,Cell biology ,Mice, Inbred C57BL ,PPAR gamma ,Tolerance induction ,IκBα ,030104 developmental biology ,Gene Expression Regulation ,chemistry ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,Immunology ,Cytokines ,Inflammation Mediators ,medicine.symptom ,Reactive Oxygen Species - Abstract
SummaryInhalation of environmental antigens such as allergens does not always induce inflammation in the respiratory tract. While antigen-presenting cells (APCs), including dendritic cells and macrophages, take up inhaled antigens, the cell-intrinsic molecular mechanisms that prevent an inflammatory response during this process, such as activation of the transcription factor NF-κB, are not well understood. Here, we show that the nuclear receptor PPARγ plays a critical role in blocking NF-κB activation in response to inhaled antigens to preserve immune tolerance. Tolerance induction promoted mitochondrial respiration, generation of H2O2, and suppression of NF-κB activation in WT, but not PPARγ-deficient, APCs. Forced restoration of H2O2 in PPARγ-deficient cells suppressed IκBα degradation and NF-κB activation. Conversely, scavenging reactive oxygen species from mitochondria promoted IκBα degradation with loss of regulatory and promotion of inflammatory T cell responses in vivo. Thus, communication between PPARγ and the mitochondria maintains immune quiescence in the airways.
- Published
- 2016
25. Do Mucosa-associated Invariant T Cells Checkmate Streptococcus pneumoniae?
- Author
-
Anuradha Ray and Prabir Ray
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Mucous Membrane ,Riboflavin ,Clinical Biochemistry ,Checkmate ,Cell Biology ,Biology ,medicine.disease_cause ,Mucosal-Associated Invariant T Cells ,Microbiology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Streptococcus pneumoniae ,medicine ,Invariant (mathematics) ,Molecular Biology ,030217 neurology & neurosurgery ,Original Research - Abstract
Streptococcus pneumoniae is an important bacterial pathogen that causes a range of noninvasive and invasive diseases. The mechanisms underlying variability in the ability of S. pneumoniae to transition from nasopharyngeal colonization to disease-causing pathogen are not well defined. Mucosal-associated invariant T (MAIT) cells are prevalent in mucosal tissues such as the airways and are believed to play an important role in the early response to infection with bacterial pathogens. The ability of MAIT cells to recognize and contain infection with S. pneumoniae is not known. In the present study, we analyzed MAIT-cell responses to infection with clinical isolates of S. pneumoniae serotype 19A, a serotype linked to invasive pneumococcal disease. We found that although MAIT cells were capable of responding to human dendritic and airway epithelial cells infected with S. pneumoniae, the magnitude of response to different serotype 19A isolates was determined by genetic differences in the expression of the riboflavin biosynthesis pathway. MAIT-cell release of cytokines correlated with differences in the ability of MAIT cells to respond to and control S. pneumoniae in vitro and in vivo in a mouse challenge model. Together, these results demonstrate first that there are genetic differences in riboflavin metabolism among clinical isolates of the same serotype and second that these likely determine MAIT-cell function in response to infection with S. pneumoniae. These differences are critical when considering the role that MAIT cells play in early responses to pneumococcal infection and determining whether invasive disease will develop.
- Published
- 2018
26. Thrombospondin-1 protects against pathogen-induced lung injury by limiting extracellular matrix proteolysis
- Author
-
Jesús Tejero, Mei Hulver, Zhenyu Cheng, Zeyu Xiong, Anuradha Ray, Michael E. Zegans, Jennifer M. Bomberger, William Bain, Jongyoon Han, Yanyan Qu, Hyunryul Ryu, Robert M. Q. Shanks, Rebecca J. Brown, Janet S. Lee, Tolani F. Olonisakin, Jill Zupetic, Prabir Ray, Joseph M. Pilewski, and Vaughn S. Cooper
- Subjects
0301 basic medicine ,Proteases ,Neutrophils ,Virulence Factors ,Proteolysis ,Inflammation ,Lung injury ,Microbiology ,Thrombospondin 1 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Bacterial Proteins ,Pneumonia, Bacterial ,Medicine ,Animals ,Humans ,Pseudomonas Infections ,Lung ,Mice, Knockout ,Innate immune system ,biology ,medicine.diagnostic_test ,business.industry ,Matricellular protein ,Metalloendopeptidases ,General Medicine ,Lung Injury ,Respiration, Artificial ,Extracellular Matrix ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,Neutrophil elastase ,Host-Pathogen Interactions ,Pseudomonas aeruginosa ,biology.protein ,medicine.symptom ,business ,Leukocyte Elastase ,Research Article - Abstract
Acute lung injury is characterized by excessive extracellular matrix proteolysis and neutrophilic inflammation. A major risk factor for lung injury is bacterial pneumonia. However, host factors that protect against pathogen-induced and host-sustained proteolytic injury following infection are poorly understood. Pseudomonas aeruginosa (PA) is a major cause of nosocomial pneumonia and secretes proteases to amplify tissue injury. We show that thrombospondin-1 (TSP-1), a matricellular glycoprotein released during inflammation, dose-dependently inhibits PA metalloendoprotease LasB, a virulence factor. TSP-1-deficient (Thbs1-/-) mice show reduced survival, impaired host defense, and increased lung permeability with exaggerated neutrophil activation following acute intrapulmonary PA infection. Administration of TSP-1 from platelets corrects the impaired host defense and aberrant injury in Thbs1-/- mice. Although TSP-1 is cleaved into 2 fragments by PA, TSP-1 substantially inhibits Pseudomonas elastolytic activity. Administration of LasB inhibitor, genetic disabling of the PA type II secretion system, or functional deletion of LasB improves host defense and neutrophilic inflammation in mice. Moreover, TSP-1 provides an additional line of defense by directly subduing host-derived proteolysis, with dose-dependent inhibition of neutrophil elastase from airway neutrophils of mechanically ventilated critically ill patients. Thus, a host matricellular protein provides dual levels of protection against pathogen-initiated and host-sustained proteolytic injury following microbial trigger.
- Published
- 2018
27. Cutting Edge: Dual Function of PPARγ in CD11c+ Cells Ensures Immune Tolerance in the Airways
- Author
-
Anupriya Khare, Mahesh Raundhal, Krishnendu Chakraborty, Anuradha Ray, and Prabir Ray
- Subjects
Regulatory T cell ,p38 mitogen-activated protein kinases ,Immunology ,CD11c ,hemic and immune systems ,chemical and pharmacologic phenomena ,Peroxisome ,Biology ,Allergic inflammation ,Cell biology ,Immune tolerance ,ALDH1A2 ,medicine.anatomical_structure ,medicine ,Immunology and Allergy ,Receptor - Abstract
The respiratory tract maintains immune homeostasis despite constant provocation by environmental Ags. Failure to induce tolerogenic responses to allergens incites allergic inflammation. Despite the understanding that APCs have a crucial role in maintaining immune tolerance, the underlying mechanisms are poorly understood. Using mice with a conditional deletion of peroxisome proliferator-activated receptor γ (PPARγ) in CD11c+ cells, we show that PPARγ performs two critical functions in CD11c+ cells to induce tolerance, thereby preserving immune homeostasis. First, PPARγ was crucial for the induction of retinaldehyde dehydrogenase (aldh1a2) selectively in CD103+ dendritic cells, which we recently showed promotes Foxp3 expression in naive CD4+ T cells. Second, in all CD11c+ cells, PPARγ was required to suppress expression of the Th17-skewing cytokines IL-6 and IL-23p19. Also, lack of PPARγ in CD11c+ cells induced p38 MAPK activity, which was recently linked to Th17 development. Thus, PPARγ favors immune tolerance by promoting regulatory T cell generation and blocking Th17 differentiation.
- Published
- 2015
28. IRF5 distinguishes severe asthma in humans and drives Th1 phenotype and airway hyperreactivity in mice
- Author
-
Seyed Mehdi Nouraie, Rachel Hannum, Christina Morse, Rachael Huff, Timothy B. Oriss, Sally E. Wenzel, Marc Gauthier, Krishnendu Chakraborty, Kathryn Scholl, Mahesh Raundhal, Sudipta Das, Anuradha Ray, and Prabir Ray
- Subjects
0301 basic medicine ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,General Medicine ,Disease ,Phenotype ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Immune system ,Pulmonology ,Internal medicine ,Immunology ,medicine ,business ,Lymph node ,Transcription factor ,IRF5 ,Research Article ,030215 immunology - Abstract
Severe asthma (SA) is a significant problem both clinically and economically, given its poor response to corticosteroids (CS). We recently reported a complex type 1-dominated (IFN-γ-dominated) immune response in more than 50% of severe asthmatics despite high-dose CS treatment. Also, IFN-γ was found to be critical for increased airway hyperreactivity (AHR) in our model of SA. The transcription factor IRF5 expressed in M1 macrophages can induce a Th1/Th17 response in cocultured human T cells. Here we show markedly higher expression of IRF5 in bronchoalveolar lavage (BAL) cells of severe asthmatics as compared with that in cells from milder asthmatics or healthy controls. Using our SA mouse model, we demonstrate that lack of IRF5 in lymph node migratory DCs severely limits their ability to stimulate the generation of IFN-γ- and IL-17-producing CD4+ T cells and IRF5-/- mice subjected to the SA model displayed significantly lower IFN-γ and IL-17 responses, albeit showing a reciprocal increase in Th2 response. However, the absence of IRF5 rendered the mice responsive to CS with suppression of the heightened Th2 response. These data support the notion that IRF5 inhibition in combination with CS may be a viable approach to manage disease in a subset of severe asthmatics.
- Published
- 2017
29. The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia
- Author
-
Valerian E. Kagan, Janet S. Lee, Timothy B. Oriss, Anupriya Khare, Rachael Huff, Claudette M. St. Croix, Mahesh Raundhal, Simon C. Watkins, Yulia Y. Tyurina, Prabir Ray, Rama K. Mallampalli, Bill B. Chen, Christina Morse, Anuradha Ray, and Krishnendu Chakraborty
- Subjects
Lipopolysaccharides ,Male ,0301 basic medicine ,Cardiolipins ,Science ,General Physics and Astronomy ,Inflammation ,Lung injury ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Pneumonia, Bacterial ,medicine ,Cardiolipin ,Animals ,Promoter Regions, Genetic ,Mice, Knockout ,Multidisciplinary ,Tumor Necrosis Factor-alpha ,Myeloid-Derived Suppressor Cells ,Bacterial pneumonia ,Sumoylation ,Sodium butyrate ,General Chemistry ,respiratory system ,medicine.disease ,Interleukin-10 ,Klebsiella Infections ,respiratory tract diseases ,3. Good health ,Histone Deacetylase Inhibitors ,Mice, Inbred C57BL ,PPAR gamma ,Klebsiella pneumoniae ,Interleukin 10 ,Pneumonia ,RAW 264.7 Cells ,030104 developmental biology ,chemistry ,Immunology ,Tumor necrosis factor alpha ,medicine.symptom ,Oxidation-Reduction - Abstract
Bacterial pneumonia is a significant healthcare burden worldwide. Failure to resolve inflammation after infection precipitates lung injury and an increase in morbidity and mortality. Gram-negative bacteria are common in pneumonia and increased levels of the mito-damage-associated molecular pattern (DAMP) cardiolipin can be detected in the lungs. Here we show that mice infected with Klebsiella pneumoniae develop lung injury with accumulation of cardiolipin. Cardiolipin inhibits resolution of inflammation by suppressing production of anti-inflammatory IL-10 by lung CD11b+Ly6GintLy6CloF4/80+ cells. Cardiolipin induces PPARγ SUMOylation, which causes recruitment of a repressive NCOR/HDAC3 complex to the IL-10 promoter, but not the TNF promoter, thereby tipping the balance towards inflammation rather than resolution. Inhibition of HDAC activity by sodium butyrate enhances recruitment of acetylated histone 3 to the IL-10 promoter and increases the concentration of IL-10 in the lungs. These findings identify a mechanism of persistent inflammation during pneumonia and indicate the potential of HDAC inhibition as a therapy., Non-resolving bacterial pneumonia results in lung tissue damage owing to overactive inflammation. Here the authors show that the mitochondrial DAMP cardiolipin contributes to persistent inflammation by SUMOylating PPARγ, which promotes binding of the corepressor NCOR/HDAC3 complex to the IL-10 promoter.
- Published
- 2017
30. An airway epithelial iNOS–DUOX2–thyroid peroxidase metabolome drives Th1/Th2 nitrative stress in human severe asthma
- Author
-
Eugene R. Bleecker, Serpil C. Erzurum, Sally E. Wenzel, John B. Trudeau, William W. Busse, Nipasiri Voraphani, Anuradha Ray, Jadranka Milosevic, A U Contreras, John Tedrow, Naftali Kaminski, Mark T. Gladwin, Deborah A. Meyers, Prabir Ray, and Jing Zhao
- Subjects
Adult ,Male ,medicine.medical_specialty ,Respiratory System ,Immunology ,Nitric Oxide Synthase Type II ,Iodide Peroxidase ,Severity of Illness Index ,Article ,Superoxide dismutase ,Interferon-gamma ,Young Adult ,chemistry.chemical_compound ,Th2 Cells ,Stress, Physiological ,Thyroid peroxidase ,Internal medicine ,medicine ,Metabolome ,Humans ,Immunology and Allergy ,Interleukin-13 ,biology ,Interleukin ,Th1 Cells ,Microarray Analysis ,Asthma ,Nitric oxide synthase ,Endocrinology ,chemistry ,biology.protein ,Female ,Peroxynitrite ,Ex vivo ,Peroxidase - Abstract
Severe refractory asthma is associated with enhanced nitrative stress. To determine the mechanisms for high nitrative stress in human severe asthma (SA), 3-nitrotyrosine (3NT) was compared with Th1 and Th2 cytokine expression. In SA, high 3NT levels were associated with high interferon (IFN)-γ and low interleukin (IL)-13 expression, both of which have been reported to increase inducible nitric oxide synthase (iNOS) in human airway epithelial cells (HAECs). We found that IL-13 and IFN-γ synergistically enhanced iNOS, nitrite, and 3NT, corresponding with increased H(2)O(2). Catalase inhibited whereas superoxide dismutase enhanced 3NT formation, supporting a critical role for H(2)O(2), but not peroxynitrite, in 3NT generation. Dual oxidase-2 (DUOX2), central to H(2)O(2) formation, was also synergistically induced by IL-13 and IFN-γ. The catalysis of nitrite and H(2)O(2) to nitrogen dioxide radical (NO(2)(•)) requires an endogenous peroxidase in this epithelial cell system. Thyroid peroxidase (TPO) was identified by microarray analysis ex vivo as a gene distinguishing HAEC of SA from controls. IFN-γ induced TPO in HAEC and small interfering RNA knockdown decreased nitrated tyrosine residues. Ex vivo, DUOX2, TPO, and iNOS were higher in SA and correlated with 3NT. Thus, a novel iNOS-DUOX2-TPO-NO(2)(•) metabolome drives nitrative stress in HAEC and likely in SA.
- Published
- 2014
31. STAT1-regulated lung MDSC-like cells produce IL-10 and efferocytose apoptotic neutrophils with relevance in resolution of bacterial pneumonia
- Author
-
K Isse, Janet S. Lee, Meenakshi Arora, Anuradha Ray, Anupriya Khare, Yvonne R. Chan, Manohar Yarlagadda, Stephanie Poe, David E. Levy, T.B. Oriss, Prabir Ray, and Rama K. Mallampalli
- Subjects
Male ,Neutrophils ,Immunology ,Apoptosis ,Inflammation ,Lung injury ,Biology ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Pneumonia, Bacterial ,medicine ,Animals ,Immunology and Allergy ,Myeloid Cells ,Tissue homeostasis ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Lung ,Bacterial pneumonia ,Interleukin ,medicine.disease ,Interleukin-10 ,respiratory tract diseases ,3. Good health ,Klebsiella pneumoniae ,Pneumonia ,Interleukin 10 ,STAT1 Transcription Factor ,medicine.anatomical_structure ,medicine.symptom ,030215 immunology - Abstract
Bacterial pneumonia remains a significant burden worldwide. Although an inflammatory response in the lung is required to fight the causative agent, persistent tissue-resident neutrophils in non-resolving pneumonia can induce collateral tissue damage and precipitate acute lung injury. However, little is known about mechanisms orchestrated in the lung tissue that remove apoptotic neutrophils to restore tissue homeostasis. In mice infected with Klebsiella pneumoniae, a bacterium commonly associated with hospital-acquired pneumonia, we show that interleukin (IL)-10 is essential for resolution of lung inflammation and recovery of mice after infection. Although IL-10(-/-) mice cleared bacteria, they displayed increased morbidity with progressive weight loss and persistent lung inflammation in the later phase after infection. A source of tissue IL-10 was found to be resident CD11b(+)Gr1(int)F4/80(+) cells resembling myeloid-derived suppressor cells (MDSCs) that appeared with a delayed kinetics after infection. These cells efficiently efferocytosed apoptotic neutrophils, which was aided by IL-10. The lung neutrophil burden was attenuated in infected signal transducer and activator of transcription 1 (STAT1)(-/-) mice with concomitant increase in the frequency of the MDSC-like cells and lung IL-10 levels. Thus, inhibiting STAT1 in combination with antibiotics may be a novel therapeutic strategy to address inefficient resolution of bacterial pneumonia.
- Published
- 2013
32. Current concepts of severe asthma
- Author
-
Prabir Ray, Timothy B. Oriss, Mahesh Raundhal, Anuradha Ray, and Sally E. Wenzel
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Severe asthma ,MEDLINE ,Disease ,macromolecular substances ,Review ,Anti-asthmatic Agent ,Severity of Illness Index ,03 medical and health sciences ,Interferon-gamma ,0302 clinical medicine ,Severity of illness ,medicine ,Animals ,Humans ,Anti-Asthmatic Agents ,Intensive care medicine ,Asthma ,Inflammation ,business.industry ,General Medicine ,Environmental exposure ,Environmental Exposure ,medicine.disease ,Clinical trial ,030104 developmental biology ,Phenotype ,Treatment Outcome ,030228 respiratory system ,Immune System ,Physical therapy ,business - Abstract
The term asthma encompasses a disease spectrum with mild to very severe disease phenotypes whose traditional common characteristic is reversible airflow limitation. Unlike milder disease, severe asthma is poorly controlled by the current standard of care. Ongoing studies using advanced molecular and immunological tools along with improved clinical classification show that severe asthma does not identify a specific patient phenotype, but rather includes patients with constant medical needs, whose pathobiologic and clinical characteristics vary widely. Accordingly, in recent clinical trials, therapies guided by specific patient characteristics have had better outcomes than previous therapies directed to any subject with a diagnosis of severe asthma. However, there are still significant gaps in our understanding of the full scope of this disease that hinder the development of effective treatments for all severe asthmatics. In this Review, we discuss our current state of knowledge regarding severe asthma, highlighting different molecular and immunological pathways that can be targeted for future therapeutic development.
- Published
- 2016
33. Full Spectrum of LPS Activation in Alveolar Macrophages of Healthy Volunteers by Whole Transcriptomic Profiling
- Author
-
Bryan J. McVerry, Robert M. Tighe, Suchitra Barge, W. Michael Foster, Anastasiya Birukova, Yutong Zhao, William Horne, Rama K. Mallampalli, Prabir Ray, Anuradha Ray, Miguel Pinilla-Vera, John W. Hollingsworth, Jay K. Kolls, Janet S. Lee, Jing Zhao, Zeyu Xiong, and Michael P. Donahoe
- Subjects
Lipopolysaccharides ,Male ,0301 basic medicine ,Interferon Regulatory Factor-7 ,medicine.medical_treatment ,lcsh:Medicine ,Biochemistry ,White Blood Cells ,Mice ,0302 clinical medicine ,Animal Cells ,Interferon ,Medicine and Health Sciences ,Small interfering RNAs ,Alveolar Macrophages ,lcsh:Science ,Regulation of gene expression ,Multidisciplinary ,Gene Ontologies ,High-Throughput Nucleotide Sequencing ,Genomics ,Middle Aged ,Healthy Volunteers ,Interleukin-10 ,Nucleic acids ,Interleukin 10 ,Cytokine ,Gene Knockdown Techniques ,Female ,Ubiquitin-Specific Proteases ,Cellular Types ,Bronchoalveolar Lavage Fluid ,Ubiquitin Thiolesterase ,Research Article ,medicine.drug ,Adult ,Adolescent ,Immune Cells ,Immunology ,Biology ,03 medical and health sciences ,Extraction techniques ,Gene Types ,Endopeptidases ,Macrophages, Alveolar ,Genetics ,medicine ,Animals ,Humans ,Non-coding RNA ,Aged ,Blood Cells ,Macrophages ,lcsh:R ,Biology and Life Sciences ,Proteins ,Computational Biology ,Cell Biology ,Macrophage Activation ,Genome Analysis ,Molecular biology ,RNA extraction ,Gene regulation ,Research and analysis methods ,RAW 264.7 Cells ,030104 developmental biology ,Gene Expression Regulation ,TRIF ,TLR4 ,RNA ,Regulator Genes ,IRF7 ,lcsh:Q ,Interferons ,Gene expression ,Transcriptome ,030215 immunology ,Interferon regulatory factors - Abstract
Despite recent advances in understanding macrophage activation, little is known regarding how human alveolar macrophages in health calibrate its transcriptional response to canonical TLR4 activation. In this study, we examined the full spectrum of LPS activation and determined whether the transcriptomic profile of human alveolar macrophages is distinguished by a TIR-domain-containing adapter-inducing interferon-β (TRIF)-dominant type I interferon signature. Bronchoalveolar lavage macrophages were obtained from healthy volunteers, stimulated in the presence or absence of ultrapure LPS in vitro, and whole transcriptomic profiling was performed by RNA sequencing (RNA-Seq). LPS induced a robust type I interferon transcriptional response and Ingenuity Pathway Analysis predicted interferon regulatory factor (IRF)7 as the top upstream regulator of 89 known gene targets. Ubiquitin-specific peptidase (USP)-18, a negative regulator of interferon α/β responses, was among the top up-regulated genes in addition to IL10 and USP41, a novel gene with no known biological function but with high sequence homology to USP18. We determined whether IRF-7 and USP-18 can influence downstream macrophage effector cytokine production such as IL-10. We show that IRF-7 siRNA knockdown enhanced LPS-induced IL-10 production in human monocyte-derived macrophages, and USP-18 overexpression attenuated LPS-induced production of IL-10 in RAW264.7 cells. Quantitative PCR confirmed upregulation of USP18, USP41, IL10, and IRF7. An independent cohort confirmed LPS induction of USP41 and IL10 genes. These results suggest that IRF-7 and predicted downstream target USP18, both elements of a type I interferon gene signature identified by RNA-Seq, may serve to fine-tune early cytokine response by calibrating IL-10 production in human alveolar macrophages.
- Published
- 2016
34. Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age at onset
- Author
-
Anuradha Ray, Chetan Naik, Sally E. Wenzel, Prabir Ray, Fernando Holguin, John M. Coleman, and John B. Trudeau
- Subjects
Adult ,Chemokine CCL11 ,Male ,Pulmonary and Respiratory Medicine ,Eotaxin ,Enzyme-Linked Immunosorbent Assay ,Inflammation ,Late onset ,Real-Time Polymerase Chain Reaction ,Bronchoalveolar Lavage ,Article ,Statistics, Nonparametric ,Adrenal Cortex Hormones ,immune system diseases ,Bronchoscopy ,Eosinophilia ,Eosinophilic ,medicine ,Humans ,Age of Onset ,Asthma ,medicine.diagnostic_test ,Chemokine CCL26 ,business.industry ,Chemokine CCL24 ,Epithelial Cells ,respiratory system ,Eosinophil ,medicine.disease ,respiratory tract diseases ,medicine.anatomical_structure ,Bronchoalveolar lavage ,Chemokines, CC ,Immunology ,Female ,medicine.symptom ,business - Abstract
Background Eosinophilic inflammation is implicated in asthma. Eotaxin 1–3 regulate eosinophil trafficking into the airways along with other chemotactic factors. However, the epithelial and bronchoalveolar lavage (BAL) cell expression of these chemokines in relation to asthma severity and eosinophilic phenotypes has not been addressed. Objective To measure the expression of the three eotaxin isoforms in bronchoscopically obtained samples and compare them with clinically relevant parameters between normal subjects and patients with asthma. Methods Normal subjects and patients with asthma of varying severity recruited through the Severe Asthma Research Program underwent clinical assessment and bronchoscopy with airway brushing and BAL. Eotaxin 1–3 mRNA/protein were measured in epithelial and BAL cells and compared with asthma severity, control and eosinophilic inflammation. Results Eotaxin-2 and eotaxin-3 mRNA and eotaxin-2 protein were increased in airway epithelial brushings from patients with asthma and were highest in cases of severe asthma (p values 0.0155, 0.0033 and 0.0006, respectively), with eotaxin-2 protein increased with age at onset. BAL cells normally expressed high levels of eotaxin-2 mRNA/protein but BAL fluid levels of eotaxin-2 were lowest in severe asthma. Epithelial eotaxin-2 and eotaxin-3 mRNA/protein was associated with sputum eosinophilia, lower forced expiratory volume in 1 s and more asthma exacerbations. Airway epithelial cell eotaxin-2 protein differed by asthma severity only in those with late onset disease, and tended to be highest in those with late onset eosinophilic asthma. Conclusions Epithelial eotaxin-2 and 3 are increased in asthma and severe asthma. Their expression may contribute to luminal migration of eosinophils, especially in later onset disease, asthma control and severity.
- Published
- 2012
35. LPS-induced CD11b+Gr1intF4/80+ regulatory myeloid cells suppress allergen-induced airway inflammation
- Author
-
Meenakshi Arora, Anuradha Ray, Prabir Ray, and Stephanie Poe
- Subjects
Adoptive cell transfer ,Allergy ,Lipopolysaccharide ,Immunology ,Inflammation ,Article ,Mice ,chemistry.chemical_compound ,Antigen ,medicine ,Animals ,Antigens, Ly ,Humans ,Immunology and Allergy ,Myeloid Cells ,Antigen-presenting cell ,Th1-Th2 Balance ,Immunosuppression Therapy ,Pharmacology ,CD11b Antigen ,business.industry ,Pneumonia ,Dendritic cell ,respiratory system ,medicine.disease ,Antigens, Differentiation ,Asthma ,respiratory tract diseases ,Disease Models, Animal ,chemistry ,TLR4 ,medicine.symptom ,business - Abstract
In humans, the bacterial product lipopolysaccharide (LPS) has been associated with protection from allergic diseases such as asthma. However, in mouse models of allergic asthma, differential effects of LPS have been noted based on the dose. A low dose of LPS promotes Th2 responses and allergic disease but a high dose has been associated with suppression of allergic airway inflammation. Our recent work has described the ability of LPS to increase the frequency of CD11b+Gr1intF4/80+ (abbreviated as Gr1int cells) cells in the lung tissue of mice in a dose-dependent fashion that is dependent on TLR4 and the TLR adaptor protein, MyD88. Both phenotypically and morphologically, the cells were found to have similarities with myeloid-derived suppressor cells. Adoptive transfer of LPS-induced Gr1int cells suppressed allergen-induced airway inflammation suggesting that these myeloid cells may have regulatory functions in allergic asthma. Although the Gr1int cells are readily detectable in the lung tissue of LPS-treated mice, they are barely detectable in the lung-draining lymph nodes (LNs) or in the airway lumen. This causes selective enrichment of these cells over dendritic cells (DCs) in the tissue since migratory DCs are induced by LPS to migrate to the draining LNs for presentation of antigen to LN T cells. The Gr1int cells were found to blunt the ability of lung DCs to upregulate GATA-3 or to promote STAT5 activation in primed Th2 cells, both transcription factors having critical roles in Th2 effector function. Thus, a complete understanding of the generation and regulation of the Gr1int cells would provide new avenues to either promote or delete these cells for disease-specific immunoregulation.
- Published
- 2011
36. Lung myeloid-derived suppressor cells and regulation of inflammation
- Author
-
Stephanie Poe, Prabir Ray, Anuradha Ray, and Meenakshi Arora
- Subjects
Lipopolysaccharides ,Lipopolysaccharide ,T-Lymphocytes ,Immunology ,Inflammation ,Allergic inflammation ,chemistry.chemical_compound ,Hypersensitivity ,medicine ,Animals ,Humans ,Immunologic Factors ,Myeloid Cells ,Lung ,Immunosuppression Therapy ,Tumor microenvironment ,business.industry ,medicine.anatomical_structure ,chemistry ,Tumor progression ,TLR4 ,Myeloid-derived Suppressor Cell ,medicine.symptom ,business - Abstract
Myeloid-derived suppressor cells (MDSCs) have been investigated largely in the context of tumor progression. In contrast to the negative connotation of MDSCs in cancer immunity, our laboratory has recently reported on the development and role of pulmonary MDSC-like cells (CD11b(+)Gr1(int)F4/80(+)) in the regulation of allergic airway inflammation. These regulatory cells were expanded in a TLR4/MyD88-dependent manner and were both phenotypically and morphologically similar to those described in the tumor microenvironment. Although bacterial lipopolysaccharide (LPS) was initially described as an adjuvant in the development of allergic inflammation, subsequent studies showed that this is true only at relatively low doses of LPS. A high dose of LPS was shown to actually suppress eosinophilic airway inflammation. In our efforts to understand the mechanism underlying LPS-mediated suppression of allergic airway disease, we recently showed that LPS induces MDSC-like cells in the lung tissue in a dose-dependent manner, with increased accumulation of the cells at high doses of LPS. In contrast to lung dendritic cells (DCs), the MDSC-like cells did not traffic to the lung-draining lymph nodes, allowing them to act in a dominant fashion over DCs in the regulation of Th2 responses. The MDSC-like cells were found to blunt the ability of the lung DCs to upregulate GATA-3 or to promote STAT5 activation in primed Th2 cells, both transcription factors having critical roles in Th2 effector function. Thus, a complete understanding of the generation and regulation of the lung MDSCs would provide novel options for therapeutic interventions.
- Published
- 2011
37. TNF-α from inflammatory dendritic cells (DCs) regulates lung IL-17A/IL-5 levels and neutrophilia versus eosinophilia during persistent fungal infection
- Author
-
Shinobu Saijo, Todd A. Reinhart, Anupriya Khare, Oded Foreman, Manohar Yarlagadda, Timothy B. Oriss, Jay K. Kolls, Beth A. Fallert Junecko, Anuradha Ray, Shizuo Akira, Yoichiro Iwakura, Mingjian Fei, Shikha Bhatia, and Prabir Ray
- Subjects
CD4-Positive T-Lymphocytes ,Neutrophils ,medicine.medical_treatment ,CD11c ,Inflammation ,Biology ,Mice ,Antigens, CD ,Eosinophilia ,medicine ,Animals ,Humans ,Lung ,Interleukin 5 ,Mice, Inbred BALB C ,Multidisciplinary ,Tumor Necrosis Factor-alpha ,Interleukin-17 ,NF-kappa B ,Dendritic Cells ,Biological Sciences ,Eosinophil ,Toll-Like Receptor 2 ,Neutrophilia ,Mice, Inbred C57BL ,Cytokine ,medicine.anatomical_structure ,Immunology ,Tumor necrosis factor alpha ,Pulmonary Aspergillosis ,Interleukin 17 ,Interleukin-5 ,medicine.symptom - Abstract
Aspergillus fumigatus is commonly associated with allergic bronchopulmonary aspergillosis in patients with severe asthma in which chronic airway neutrophilia predicts a poor outcome. We were able to recapitulate fungus-induced neutrophilic airway inflammation in a mouse model in our efforts to understand the underlying mechanisms. However, neutrophilia occurred in a mouse strain-selective fashion, providing us with an opportunity to perform a comparative study to elucidate the mechanisms involved. Here we show that TNF-α, largely produced by Ly6c + CD11b + dendritic cells (DCs), plays a central role in promoting IL-17A from CD4 + T cells and collaborating with it to induce airway neutrophilia. Compared with C57BL/6 mice, BALB/c mice displayed significantly more TNF-α–producing DCs and macrophages in the lung. Lung TNF-α levels were drastically reduced in CD11c-DTR BALB/c mice depleted of CD11c+ cells, and TNF-α–producing Ly6c + CD11b + cells were abolished in Dectin-1 −/− and MyD88 −/− BALB/c mice. TNF-α deficiency itself blunted accumulation of inflammatory Ly6c + CD11b + DCs. Also, lack of TNF-α decreased IL-17A but promoted IL-5 levels, switching inflammation from a neutrophil to eosinophil bias resembling that in C57BL/6 mice. The TNF-α low DCs in C57BL/6 mice contained more NF-κB p50 homodimers, which are strong repressors of TNF-α transcription. Functionally, collaboration between TNF-α and IL-17A triggered significantly higher levels of the neutrophil chemoattractants keratinocyte cytokine and macrophage inflammatory protein 2 in BALB/c mice. Our study identifies TNF-α as a molecular switch that orchestrates a sequence of events in DCs and CD4 T cells that promote neutrophilic airway inflammation.
- Published
- 2011
38. Inhibition and Role of let-7d in Idiopathic Pulmonary Fibrosis
- Author
-
Prabir Ray, Manohar Yarlagadda, Thomas J. Richards, Annie Pardo, Kevin F. Gibson, Kusum Pandit, Ahmi Ben-Yehudah, Mandal K. Singh, Daniel Handley, Moisés Selman, Argyris Tzouvelekis, Simon C. Watkins, David L. Corcoran, Naftali Kaminski, Panayiotis V. Benos, Hanadie Yousef, Demosthenes Bouros, Samuel A. Yousem, Kazuhisa Konishi, and Oliver Eickelberg
- Subjects
Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Down-Regulation ,In situ hybridization ,Biology ,Critical Care and Intensive Care Medicine ,Immunofluorescence ,Polymerase Chain Reaction ,Mice ,Idiopathic pulmonary fibrosis ,chemistry.chemical_compound ,Transforming Growth Factor beta ,microRNA ,Pulmonary fibrosis ,F. Interstitial Lung Disease ,medicine ,Animals ,Humans ,Vimentin ,S100 Calcium-Binding Protein A4 ,Electrophoretic mobility shift assay ,Antagomir ,Smad3 Protein ,Lung ,Cells, Cultured ,In Situ Hybridization ,medicine.diagnostic_test ,HMGA2 Protein ,S100 Proteins ,Epithelial Cells ,respiratory system ,Cadherins ,medicine.disease ,Molecular biology ,Actins ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,Mice, Inbred C57BL ,Pulmonary Alveoli ,MicroRNAs ,chemistry ,sense organs ,Chromatin immunoprecipitation - Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal fibrotic lung disease characterized by profound changes in epithelial cell phenotype and fibroblast proliferation.To determine changes in expression and role of microRNAs in IPF.RNA from 10 control and 10 IPF tissues was hybridized on Agilent microRNA microarrays and results were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. SMAD3 binding to the let-7d promoter was confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assay, luciferase assays, and reduced expression of let-7d in response to transforming growth factor-beta. HMGA2, a let-7d target, was localized by immunohistochemistry. In mice, let-7d was inhibited by intratracheal administration of a let-7d antagomir and its effects were determined by immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, and morphometry.Eighteen microRNAs including let-7d were significantly decreased in IPF. Transforming growth factor-beta down-regulated let-7d expression, and SMAD3 binding to the let-7d promoter was demonstrated. Inhibition of let-7d caused increases in mesenchymal markers N-cadherin-2, vimentin, and alpha-smooth muscle actin (ACTA2) as well as HMGA2 in multiple epithelial cell lines. let-7d was significantly reduced in IPF lungs and the number of epithelial cells expressing let-7d correlated with pulmonary functions. HMGA2 was increased in alveolar epithelial cells of IPF lungs. let-7d inhibition in vivo caused alveolar septal thickening and increases in collagen, ACTA2, and S100A4 expression in SFTPC (pulmonary-associated surfactant protein C) expressing alveolar epithelial cells.Our results indicate a role for microRNAs in IPF. The down-regulation of let-7d in IPF and the profibrotic effects of this down-regulation in vitro and in vivo suggest a key regulatory role for this microRNA in preventing lung fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT 00258544).
- Published
- 2010
39. STAT1 and Glucocorticoid Receptor Interaction: Mechanism for Steroid Insensitivity in Type 1 High Severe Asthma
- Author
-
Timothy B. Oriss, Sally E. Wenzel, Prabir Ray, Anuradha Ray, Marc Gauthier, and Krishnendu Chakraborty
- Subjects
0301 basic medicine ,medicine.medical_specialty ,biology ,Mechanism (biology) ,Chemistry ,Severe asthma ,medicine.medical_treatment ,Immunology ,Steroid ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Glucocorticoid receptor ,Endocrinology ,030228 respiratory system ,Internal medicine ,medicine ,biology.protein ,Immunology and Allergy ,STAT1 - Published
- 2018
40. Hepatocyte Growth Factor Inhibits Epithelial to Myofibroblast Transition in Lung Cells via Smad7
- Author
-
Manasi N. Shukla, Kira L. Lathrop, Prabir Ray, Rabindranath Ray, Anuradha Ray, and Jane L. Rose
- Subjects
Pulmonary and Respiratory Medicine ,MAP Kinase Signaling System ,Pulmonary Fibrosis ,Clinical Biochemistry ,SMAD ,Epithelium ,Smad7 Protein ,Bleomycin ,Mice ,Transforming Growth Factor beta ,medicine ,Animals ,Epithelial–mesenchymal transition ,Fibroblast ,Lung ,Molecular Biology ,biology ,Hepatocyte Growth Factor ,Muscle, Smooth ,Articles ,Cell Biology ,Transforming growth factor beta ,Fibroblasts ,Actins ,Rats ,Cell biology ,Fibronectin ,Phenotype ,medicine.anatomical_structure ,biology.protein ,Hepatocyte growth factor ,Myofibroblast ,medicine.drug ,Transforming growth factor - Abstract
Idiopathic pulmonary fibrosis is a lethal parenchymal lung disease characterized by denudation of the lung epithelium, fibroblast proliferation, and collagen deposition. Cellular changes underlying disease progression involve injury to alveolar epithelial cells, epithelial to mesenchymal transition, proliferation of alpha-smooth muscle actin (alpha-SMA)-expressing myofibroblasts and of fibroblasts resulting in enhanced deposition of extracellular matrix proteins. Hepatocyte growth factor (HGF) inhibits progression of bleomycin-induced pulmonary fibrosis in mice. The mechanism underlying the inhibitory effect of HGF was investigated in an in vitro model. We show that HGF markedly antagonizes basal and transforming growth factor (TGF)-beta-induced expression of myofibroblast markers such as alpha-SMA, collagen type 1, and fibronectin in rat alveolar epithelial cells. HGF also inhibited TGF-beta-induced alpha-SMA expression in primary murine alveolar epithelial cells. Since TGF-beta is known to regulate alpha-SMA expression, the effect of HGF on components of TGF-beta signaling was investigated. HGF induced expression of Smad7, an inhibitor of TGF-beta signaling, in a mitogen-activated protein kinase-dependent manner. HGF also induced the nuclear export of Smad7 and Smad ubiquitin regulatory factor 1 (Smurf1) to the cytoplasm. HGF-dependent decrease in alpha-SMA was abolished with specific siRNAs targeted to Smad7. Thus, induction of Smad7 by HGF serves to limit acquisition of the myofibroblast phenotype in alveolar epithelial cells.
- Published
- 2009
41. Indoleamine 2,3-dioxygenase in lung dendritic cells promotes Th2 responses and allergic inflammation
- Author
-
Hui Xu, Prabir Ray, Li Chen, Barbro N. Melgert, Mingjian Fei, Timothy B. Oriss, Charles G. Irvin, Anuradha Ray, David H. Munn, Andrew L. Mellor, Adam C. Henry, Faculteit Medische Wetenschappen/UMCG, Groningen Research Institute for Asthma and COPD (GRIAC), and Biopharmaceuticals, Discovery, Design and Delivery (BDDD)
- Subjects
CD4(+) T-CELLS ,Myeloid ,AIRWAY INFLAMMATION ,Lymphocyte Activation ,Immunoglobulin E ,INHALED ANTIGEN ,DC ,Immune tolerance ,IDO ,ACTIVATION ,Epitopes ,Mice ,Medicine ,Indoleamine 2,3-dioxygenase ,Lung ,Multidisciplinary ,biology ,Biological Sciences ,respiratory system ,TRYPTOPHAN CATABOLISM ,medicine.anatomical_structure ,Cytokines ,Lymph ,Bronchial Hyperreactivity ,medicine.symptom ,EXPRESSION ,TUMOR-INDUCED TOLERANCE ,Inflammation ,Allergic inflammation ,Cross-Priming ,Th2 Cells ,Antigen ,Hypersensitivity ,Immune Tolerance ,Animals ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,tryptophan ,Antigens ,EXPERIMENTAL ASTHMA ,Cell Proliferation ,business.industry ,BOUND TGF-BETA ,Dendritic Cells ,asthma ,respiratory tract diseases ,Disease Models, Animal ,Chronic Disease ,Immunology ,biology.protein ,Lymph Nodes ,business ,airways - Abstract
Indoleamine 2,3 dioxygenase (IDO) has emerged as an important mediator of immune tolerance via inhibition of Th1 responses. However, the role of IDO in antigen-induced tolerance or allergic inflammation in the airways that is regulated by Th2 responses has not been elucidated. By using IDO −/− mice, we found no impairment of airway tolerance, but, surprisingly, absence of IDO provided significant relief from establishment of allergic airways disease, as evident from attenuated Th2 cytokine production, airway inflammation, mucus secretion, airway hyperresponsiveness, and serum ovalbumin-specific IgE. Myeloid dendritic cells isolated from lung-draining lymph nodes of mice immunized for either Th1 or Th2 response revealed fewer mature dendritic cells in the lymph nodes of IDO −/− mice. However, the net functional impact of IDO deficiency on antigen-induced responses was more remarkable in the Th2 model than in the Th1 model. Collectively, these data suggest that IDO is not required for the induction of immune tolerance in the airways but plays a role in promoting Th2-mediated allergic airway inflammation via unique effects on lung dendritic cells.
- Published
- 2008
42. High IFN-γ and low SLPI mark severe asthma in mice and humans
- Author
-
Joseph M. Pilewski, Rachael Huff, Timothy B. Oriss, Christina Morse, Sally E. Wenzel, Jay K. Kolls, Prabir Ray, Anupriya Khare, Mahesh Raundhal, Fernando Holguin, Anuradha Ray, Jadranka Milosevic, and John B. Trudeau
- Subjects
Adult ,Male ,Adolescent ,Bronchoalveolar Lavage ,Severity of Illness Index ,Interferon-gamma ,Mice ,Immune system ,Th2 Cells ,medicine ,Animals ,Humans ,Interferon gamma ,Secretory Leukocyte Peptidase Inhibitor ,Receptor ,Lung ,Asthma ,Mice, Knockout ,Mice, Inbred BALB C ,Receptors, Interleukin-17 ,medicine.diagnostic_test ,business.industry ,Interleukin-17 ,General Medicine ,Middle Aged ,Th1 Cells ,medicine.disease ,respiratory tract diseases ,3. Good health ,Disease Models, Animal ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Gene Expression Regulation ,Immunology ,Interleukin 17 ,business ,SLPI ,medicine.drug - Abstract
Severe asthma (SA) is a challenge to control, as patients are not responsive to high doses of systemic corticosteroids (CS). In contrast, mild-moderate asthma (MMA) is responsive to low doses of inhaled CS, indicating that Th2 cells, which are dominant in MMA, do not solely orchestrate SA development. Here, we analyzed broncholalveolar lavage cells isolated from MMA and SA patients and determined that IFN-γ (Th1) immune responses are exacerbated in the airways of individuals with SA, with reduced Th2 and IL-17 responses. We developed a protocol that recapitulates the complex immune response of human SA, including the poor response to CS, in a murine model. Compared with WT animals, Ifng–/– mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. Conversely, AHR was not reduced in Il17ra–/– mice, although airway inflammation was lower. Computer-assisted pathway analysis tools linked IFN-γ to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells, and IFN-γ inversely correlated with SLPI expression in SA patients and the mouse model. In mice subjected to our SA model, forced SLPI expression decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Our study identifies a distinct immune response in SA characterized by a dysregulated IFN-γ/SLPI axis that affects lung function.
- Published
- 2015
43. LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1
- Author
-
Sudipta Das, Sruti Shiva, Bill B. Chen, Yulia Y. Tyurina, Yuan Liu, Prabir Ray, Matthew J. Synan, Jianfei Jiang, Valerian E. Kagan, Chunbin Zou, Michelle L. Manni, Janet S. Lee, Yutong Zhao, Rama K. Mallampalli, Jin Li, Sheng Xiong, and Anuradha Ray
- Subjects
Lipopolysaccharides ,Cardiolipins ,Proteolysis ,Histone Deacetylase 2 ,Mitochondrion ,Models, Biological ,Epithelium ,Cell Line ,Mice ,chemistry.chemical_compound ,Ubiquitin ,Cardiolipin ,medicine ,Animals ,Gene Silencing ,SKP Cullin F-Box Protein Ligases ,biology ,medicine.diagnostic_test ,Histone deacetylase 2 ,Lysine ,Ubiquitination ,Cell Biology ,Molecular biology ,Mitochondria ,Ubiquitin ligase ,Oxygen ,chemistry ,Acetylation ,Cell culture ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Lysosomes ,Acyltransferases ,Research Article - Abstract
Cardiolipin (also known as PDL6) is an indispensable lipid required for mitochondrial respiration that is generated through de novo synthesis and remodeling. Here, the cardiolipin remodeling enzyme, acyl-CoA:lysocardiolipin-acyltransferase-1 (Alcat1; SwissProt ID, Q6UWP7) is destabilized in epithelia by lipopolysaccharide (LPS) impairing mitochondrial function. Exposure to LPS selectively decreased levels of carbon 20 (C20)-containing cardiolipin molecular species, whereas the content of C18 or C16 species was not significantly altered, consistent with decreased levels of Alcat1. Alcat1 is a labile protein that is lysosomally degraded by the ubiquitin E3 ligase Skp-Cullin-F-box containing the Fbxo28 subunit (SCF-Fbxo28) that targets Alcat1 for monoubiquitylation at residue K183. Interestingly, K183 is also an acetylation-acceptor site, and acetylation conferred stability to the enzyme. Histone deacetylase 2 (HDAC2) interacted with Alcat1, and expression of a plasmid encoding HDAC2 or treatment of cells with LPS deacetylated and destabilized Alcat1, whereas treatment of cells with a pan-HDAC inhibitor increased Alcat1 levels. Alcat1 degradation was partially abrogated in LPS-treated cells that had been silenced for HDAC2 or treated with MLN4924, an inhibitor of Cullin-RING E3 ubiquitin ligases. Thus, LPS increases HDAC2-mediated Alcat1 deacetylation and facilitates SCF-Fbxo28-mediated disposal of Alcat1, thus impairing mitochondrial integrity.
- Published
- 2015
44. Distinct Responses of Lung and Spleen Dendritic Cells to the TLR9 Agonist CpG Oligodeoxynucleotide
- Author
-
Timothy B. Oriss, Nandini Krishnamoorthy, Anuradha Ray, Prabir Ray, Li Chen, Meenakshi Arora, and Manohar Yarlagadda
- Subjects
Male ,CpG Oligodeoxynucleotide ,medicine.medical_treatment ,Immunology ,Mice, Transgenic ,Spleen ,Cell Separation ,Proinflammatory cytokine ,Mice ,Adjuvants, Immunologic ,medicine ,Animals ,Immunology and Allergy ,Lung ,Cells, Cultured ,Mice, Knockout ,Mice, Inbred BALB C ,CD40 ,biology ,Pattern recognition receptor ,TLR9 ,hemic and immune systems ,Dendritic Cells ,respiratory system ,Mice, Inbred C57BL ,Cytokine ,medicine.anatomical_structure ,Oligodeoxyribonucleotides ,Toll-Like Receptor 9 ,biology.protein ,TLR4 ,CpG Islands - Abstract
Dendritic cells (DCs) sense various components of invading pathogens via pattern recognition receptors such as TLRs. CpG oligodeoxynucleotides (ODNs), which mimic bacterial DNA, inhibit allergic airways disease and promote responses in the spleen to bacterial components. Because many TLR agonists are currently being tested for potential therapeutic effects, it is important to characterize the expression and function of TLRs in different tissues. We show that both myeloid and plasmacytoid DCs in the spleen express TLR9, the receptor for CpG ODNs, but lung DCs show no detectable expression in either subset. TLR4 expression in contrast was detected on both lung and spleen DCs. LPS was superior to CpG ODN in increasing the allostimulatory potential of lung DCs and their expression of CD40. However, both agonists efficiently stimulated spleen DCs. CpG ODNs administered to mice efficiently inhibited Th2 cytokine production both in the lung draining lymph node and in the spleen. Surprisingly, inhibition of Th2 cytokine production was evident despite high levels of expression of GATA-3 and additional transcription factors that regulate Th2 responses. Although in the spleen CpG ODNs induced IL-6, a key cytokine induced via TLR9-MyD88 signaling, no IL-6 was detectable in lung LN cells. These studies show for the first time that lung DCs lack TLR9 expression, but, despite this deficiency, CpG ODNs induce potent inhibitory effects on Th2 cytokine production in the lung without inducing expression of the proinflammatory cytokine, IL-6, which has been linked to chronic diseases in the lung and the gut.
- Published
- 2006
45. Protection of Epithelial Cells by Keratincoyte Growth Factor Signaling
- Author
-
Prabir Ray
- Subjects
Pulmonary and Respiratory Medicine ,Fibroblast Growth Factor 7 ,medicine.medical_treatment ,Apoptosis ,Mice, Transgenic ,Respiratory Mucosa ,Protein Serine-Threonine Kinases ,Lung injury ,Biology ,Fibroblast growth factor ,Ribosomal Protein S6 Kinases, 90-kDa ,Mice ,chemistry.chemical_compound ,medicine ,Animals ,Lung ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Growth factor ,Acute Lung Injury/Adult Respiratory Distress Syndrome ,Cell biology ,Oxidative Stress ,p21-Activated Kinases ,chemistry ,Cancer research ,Keratinocyte growth factor ,Signal transduction ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Oxidative injury to the lung is associated with widespread injury to the alveolar epithelium, which can be fatal unless the process is controlled and repaired. Keratinocyte growth factor (KGF), a member of the fibroblast growth factor family, has been shown to protect the lung from a variety of oxidative insults. The mechanism(s) underlying the protective effects of KGF in lung injury is being investigated in many laboratories. Although KGF has potent mitogenic effects on epithelial cells, the proliferative effect of KGF was shown to be abolished in oxygen-breathing animals, but KGF was still able to inhibit alveolar damage. This demonstrates that the protective effect of KGF cannot simply be explained by the ability of KGF to stimulate type II cell proliferation. To identify the mechanisms involved in the protective effects of KGF, we used an inducible lung-specific transgenic approach to overexpress KGF in murine lungs, since constitutive overexpression of KGF in the mouse affects lung development. The transgenic system allowed us to identify the pro-survival Akt pathway as an important mediator of the protective effects of KGF both in vivo and in vitro. In addition, use of a yeast two-hybrid system led to the identification two proteins p90RSK and PAK4 that associate with the KGF receptor and are important for the protective functions of KGF. Experiments are underway to determine whether the different pathways triggered by KGF all converge on the Akt pathway, or whether they independently induce protective mechanisms that along with Akt are crucial for cell survival.
- Published
- 2005
46. Idiopathic Pulmonary Fibrosis
- Author
-
Naftali Kaminski, Tim D. Oury, Hiroe Sato, Robert M. Rogers, Maria Stern, Annie Pardo, Peter B. Bitterman, Samuel A. Yousem, Diane C. Strollo, Sem H. Phan, Cheryl L. Fattman, Andrew Perez, Roland M. du Bois, John A. Belperio, Valerian E. Kagan, Jan C. Grutters, Maximilian MacPherson, Sanja Dacic, Frank A. Witzmann, Lana E. Hanford, Vladimir A. Tyurin, Susan Land, Zuzana Valnickova, Lisa M. Schaefer, Marcella Martinelli, Nicole Manning, Danielle Morse, Brooke T. Mossman, Paul W. Noble, Michael P. Keane, James E. Loyd, Steven L. Kunkel, David R. Moller, Nicolas Heintz, Norma J. Nowak, Li Chen, Cory M. Hogaboam, Luca Scapoli, Augustine M.K. Choi, Robert M. Strieter, James H. Dauber, Moisés Selman, Stephen W. Chensue, Maria E. Ramos-Nino, Thomas L. Petty, Brian Manning, Peter M. Henson, Jan J. Enghild, Nicholas W. Lukacs, Kenneth I. Welsh, Prabir Ray, and Astrid Haegens
- Subjects
Pulmonary and Respiratory Medicine ,0303 health sciences ,Pathology ,medicine.medical_specialty ,business.industry ,Clinical Biochemistry ,Cell Biology ,medicine.disease ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,030228 respiratory system ,Medicine ,business ,Molecular Biology ,030304 developmental biology - Published
- 2003
47. An important regulatory role for CD4 + CD8αα T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease
- Author
-
Anuradha Ray, Mathew M. Augustine, Kim Bottomly, Jyoti Das, Gobardhan Das, and Prabir Ray
- Subjects
CD4-Positive T-Lymphocytes ,T cell ,Population ,GATA3 Transcription Factor ,CD8-Positive T-Lymphocytes ,Biology ,Lymphocyte Activation ,Inflammatory bowel disease ,Mice ,Intestinal mucosa ,Antigen ,medicine ,Animals ,Intestinal Mucosa ,education ,Mice, Inbred BALB C ,education.field_of_study ,Multidisciplinary ,NF-kappa B ,Biological Sciences ,Inflammatory Bowel Diseases ,NFKB1 ,medicine.disease ,Intestinal epithelium ,DNA-Binding Proteins ,medicine.anatomical_structure ,Immunology ,Trans-Activators ,Intraepithelial lymphocyte - Abstract
The normal immunoregulatory mechanisms that maintain homeostasis in the intestinal mucosa, despite continuous provocation by environmental antigens, are jeopardized in inflammatory bowel diseases. Although previous studies have suggested that intestinal intraepithelial lymphocytes prevent spontaneous intestinal inflammation, there is limited knowledge about the characteristics of regulatory cells in the intestinal intraepithelial lymphocytes population. Here we show that CD4 + CD8αα + double-positive cells present in the intestinal intraepithelial lymphocytes population can suppress T helper 1-induced intestinal inflammation in an IL-10-dependent fashion. CD4 + T cells stimulated along the Th2 but not the Th1 lineage, when transferred to RAG-1−/− mice, acquire CD8αα expression on reaching the intestinal epithelium, and on arrival there, augment their production of IL-10. We show that a precursor CD4 + T cell after limited, but not repeated, stimulation by IL-4 is able to become a double-positive-regulatory cell on exposure to the intestinal microenvironment in mice. Both CD8αα acquisition and IL-10 production depend critically on the NF-κB-GATA-3-axis that we have previously shown is essential for differentiation to the Th2 phenotype and for the induction of airway inflammation. Our studies identify a mechanism for the generation of regulatory T cells in the intestine that may play an important role in controlling inflammatory bowel disease.
- Published
- 2003
48. Understanding Steroid-Refractory Severe Asthma
- Author
-
Mahesh Raundhal, Marc Gauthier, Sally E. Wenzel, Anuradha Ray, T.B. Oriss, and Prabir Ray
- Subjects
medicine.medical_specialty ,business.industry ,Internal medicine ,Severe asthma ,Immunology ,Immunology and Allergy ,Medicine ,Steroid refractory ,business - Published
- 2017
49. Infections in 'noninfectious' lung diseases
- Author
-
James M. Beck, Matthew R. Gingo, Sanjay Sethi, Meghan Fitzpatrick, Charles L. Daley, and Prabir Ray
- Subjects
Pulmonary and Respiratory Medicine ,Lung ,Bronchiectasis ,biology ,Respiratory tract infections ,business.industry ,Incidence ,Pittsburgh Lung Conference ,biology.organism_classification ,medicine.disease ,medicine.disease_cause ,Global Health ,Obstructive lung disease ,Haemophilus influenzae ,Pathogenesis ,Pulmonary Disease, Chronic Obstructive ,medicine.anatomical_structure ,Immunology ,Etiology ,medicine ,Humans ,Nontuberculous mycobacteria ,business ,Respiratory Tract Infections - Abstract
Many chronic pulmonary diseases, including those that are not primarily infectious in etiology, have some aspects of their pathogenesis that are influenced by infectious organisms. Microorganisms may contribute to chronic lung diseases, either directly (i.e., overt infection) or indirectly, via the amplification of inflammatory pathways that are critical to host defense. As techniques for detecting and characterizing microorganisms have advanced, investigations of both infecting and colonizing organisms have yielded new insights into mechanisms of pulmonary disease. In addition, changes in patterns of infection and microbial resistance have important implications for treatment. Examples of these infectious–pulmonary associations, including Haemophilus influenzae infection and chronic obstructive pulmonary disease, nontuberculous mycobacteria and bronchiectasis, and human immunodeficiency virus and obstructive lung disease, are reviewed.
- Published
- 2014
50. Cutting Edge: MMP-9 inhibits IL-23p19 expression in dendritic cells by targeting membrane stem cell factor affecting lung IL-17 response
- Author
-
Timothy B. Oriss, Christina Morse, Anupriya Khare, Rachael Huff, Mahesh Raundhal, Krishnendu Chakraborty, Nandini Krishnamoorthy, Anuradha Ray, and Prabir Ray
- Subjects
Immunology ,Stem cell factor ,chemical and pharmacologic phenomena ,Biology ,Matrix metalloproteinase ,Article ,Mice ,Gene expression ,medicine ,Immunology and Allergy ,Animals ,Phosphorylation ,Lung ,Regulation of gene expression ,Mice, Knockout ,Stem Cell Factor ,Cell Membrane ,Interleukin-17 ,hemic and immune systems ,Dendritic Cells ,Th1 Cells ,Cell biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Matrix Metalloproteinase 9 ,Cancer research ,Interleukin-23 Subunit p19 ,Th17 Cells ,Bone marrow ,Interleukin 17 ,Proto-Oncogene Proteins c-akt ,Intracellular - Abstract
We reported previously that c-kit ligation by membrane-bound stem cell factor (mSCF) boosts IL-6 production in dendritic cells (DCs) and a Th17-immune response. However, Th17 establishment also requires heterodimeric IL-23, but the mechanisms that regulate IL-23 gene expression in DCs are not fully understood. We show that IL-23p19 gene expression in lung DCs is dependent on mSCF, which is regulated by the metalloproteinase MMP-9. Th1-inducing conditions enhanced MMP-9 activity, causing cleavage of mSCF, whereas the opposite was true for Th17-promoting conditions. In MMP-9−/− mice, a Th1-inducing condition could maintain mSCF and enhance IL-23p19 in DCs, promoting IL-17–producing CD4+ T cells in the lung. Conversely, mSCF cleavage from bone marrow DCs in vitro by rMMP-9 led to reduced IL-23p19 expression under Th17-inducing conditions, with dampening of intracellular AKT phosphorylation. Collectively, these results show that the c-kit/mSCF/MMP-9 axis regulates IL-23 gene expression in DCs to control IL-17 production in the lung.
- Published
- 2014
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.