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BACKGROUND CD48 is a costimulatory receptor of the immune response. Interactions between CD48 and CD244 (2B4) on mast cells and eosinophils suggest that these cells can act synergistically in the 'allergic effector unit' to promote inflammation. This report explores the role of CD48 in persistent allergic (PAR) and non-allergic rhinitis (NAR). METHODS In this study, serum was obtained from 70 subjects (45 female, 64%; mean age, 36; range 18-70 years) to estimate the levels of sCD48 and two eosinophils-related parameters, ECP and eotaxin-1/CCL11. Twenty patients with PAR, 15 patients with NAR, and 35 healthy controls were included. The intensity of rhinitis symptoms was estimated by the Total Nasal Symptom Score. We also assessed the fractional exhaled nitric oxide bronchial and nasal fractions (FeNO) and neutrophil to lymphocyte (NLR) and eosinophil to lymphocyte (ELR) ratios. RESULTS Significantly higher sCD48 serum levels were observed in the NAR group than in the PAR and control groups, and significant correlations were found between the serum level of sCD48 and the number and percentage of eosinophils. ECP and eotaxin-1/CCL11 serum levels were also found to be significantly higher in the NAR group. CONCLUSIONS CD48 may be involved in eosinophilic pathophysiological reactions in non-allergic rhinitis.

Background Mycoplasma pneumoniae is one of the major pathogens causing community-acquired pneumonia in children. Although usually self-limited, Mycoplasma pneumoniae pneumonia (MPP) may lead to complicated morbidity that can even be life-threatening. Upon MPP infection, alveolar macrophage becomes attracted and activated and will induce subsequent cytokine and chemokine reaction. Refractory Mycoplasma pneumoniae pneumonia (RMPP) is manifested by clinical or radiological deterioration despite proper antibiotic therapy. RMPP is characterized with excessive inflammation and may need subsequent glucocorticoid treatment. Aim: The aim of this study was to investigate the change of plasma chemokines in non-refractory Mycoplasma pneumoniae pneumonia (NRMPP) and RMPP before and after antibiotic or methylprednisolone treatment. Method A total of 42 children with MPP were enrolled in this study. Plasma specimens were collected at admission and one to two weeks after antibiotic or methylprednisolone treatment with declined fever. Plasma specimens were then indicated to chemokines detection. Results Mycoplasma pneumoniae pneumonia altered the chemokine profile through the observation of decreased plasma M1 related chemokines (CCL2, CCL8 and CXCL10) and increased M2 related chemokines (CCL17 and CCL22) after treatment.When the patients were divided into RMPP and NRMPP groups and the chemokines before treatment were compared, the RMPP group showed higher CXCL10 but lower CCL3 and CCL11 than the NRMPP group. Conclusion Unique changes in macrophage related chemokines is observed in the course of MPP infection. NRMPP and RMPP infection in children showed distinct manifestation in chemokine profiles.

Cutaneous leishmaniasis (CL) is a neglected tropical disease with severe morbidity and socioeconomic sequelae. A better understanding of underlying immune mechanisms that lead to different clinical outcomes of CL could inform the rational design of intervention measures. While transcriptomic analyses of CL lesions were recently reported by us and others, there is a dearth of information on the expression of immune-related genes in the blood of CL patients. Herein, we investigated immune-related gene expression in whole blood samples collected from individuals with different clinical stages of CL along with healthy volunteers in an endemic CL region where Leishmania (L.) tropica is prevalent. Study participants were categorized into asymptomatic (LST+) and healthy uninfected (LST-) groups based on their leishmanin skin test (LST). Whole blood PAXgene samples were collected from volunteers, who had healed CL lesions, and patients with active L. tropica cutaneous lesions. Quality RNA extracted from 57 blood samples were subjected to Dual-color reverse-transcription multiplex ligation-dependent probe amplification (dcRT-MLPA) assay for profiling 144 immune-related genes. Results show significant changes in the expression of genes involved in interferon signaling pathway in the blood of active CL patients, asymptomatics and healed individuals. Nonetheless, distinct profiles for several immune-related genes were identified in the healed, the asymptomatic, and the CL patients compared to the healthy controls. Among others, IFI16 and CCL11 were found as immune transcript signatures for the healed and the asymptomatic individuals, respectively. These results warrant further exploration to pinpoint novel blood biomarkers for different clinical stages of CL.

Background Early detection and prognostic prediction are crucial in improving the survival of patients with head and neck squamous cell carcinoma (HNSCC). Therefore, we provided potential molecular markers in this study for early diagnosis and prognosis of this cancer based on The Cancer Genome Atlas (TCGA) database analysis and experimental validations. Methods Differentially expressed genes (DEGs) between HNSCC tumor and normal samples were identified by TCGA database-based analyses. Univariate and multivariate Cox regression analyses were applied, respectively, to identify survival-related DEGs and independent prognostic factors in HNSCC. Further, RT-qPCR was employed to verify expression of DEGs in cancer and adjacent tissues from HNSCC patients recruited in our hospital, in which we also clarified the correlation between candidate genes and clinicopathological characteristics and prognosis of HNSCC patients. Results TCGA data analyses yielded 59 DEGs. Cox analyses identified 13 candidate genes closely related to prognosis of HNSCC patients and established a five-gene signature comprising AC103702.2, LINC00941, RPL29, FOXL2, and CCL11. This five-gene signature could classify patients into high- and low-risk groups. The survival rate of the high-risk group was significantly lower than that of the low-risk group. Clinical tissue experiments further confirmed that AC103702.2, LINC00941, CCL11, and RPL29P19 genes were inversely associated with the prognosis of HNSCC patients, while CCL11 gene was positively associated. We also found that high-risk HNSCC patients presented a higher incidence of lymph node metastasis. Conclusion Five prognostic marker genes (AC103702.2, LINC00941, CCL11, RPL29P19, and FOXL2) as a gene cluster may serve as prognostic marker genes in HNSCC.

Background Obesity is a risk factor for the development of asthma. However, pharmacologic therapeutic strategies that specifically target obese asthmatics have not been identified. We hypothesize that glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) treatment inhibits aeroallergen‐induced early innate airway inflammation in a mouse model of asthma in the setting of obesity. Methods SWR (lean) and TALLYHO (obese) mice were challenged intranasally with Alternaria alternata extract (Alt‐Ext) or PBS for 4 consecutive days concurrent with GLP‐1RA or vehicle treatment. Results TALLYHO mice had greater Alt‐Ext‐induced airway neutrophilia and lung protein expression of IL‐5, IL‐13, CCL11, CXCL1, and CXCL5, in addition to ICAM‐1 expression on lung epithelial cells compared with SWR mice, and all endpoints were reduced by GLP‐1RA treatment. Alt‐Ext significantly increased BALF IL‐33 in both TALLYHO and SWR mice compared to PBS challenge, but there was no difference in the BALF IL‐33 levels between these two strains. However, TALLYHO, but not SWR, mice had significantly higher airway TSLP in BALF following Alt‐Ext challenge compared to PBS, and BALF TSLP was significantly greater in TALLYHO mice compared to SWR mice following airway Alt‐Ext challenge. GLP‐1RA treatment significantly decreased the Alt‐Ext‐induced TSLP and IL‐33 release in TALLYHO mice. While TSLP or ST2 inhibition with a neutralizing antibody decreased airway eosinophils, they did not reduce airway neutrophils in TALLYHO mice. Conclusions These results suggest that GLP‐1RA treatment may be a novel pharmacologic therapeutic strategy for obese persons with asthma by inhibiting aeroallergen‐induced neutrophilia, a feature not seen with either TSLP or ST2 inhibition., Polygenic obese mice have larger level of Altrernaria extract‐induced TSLP, the number of lung ILC2, neutrophils in the airway, and ICAM‐1 on lung epithelial cells compared with lean mice. GLP‐1RA decreases the Altrernaria extract‐induced IL‐33 and TSLP release, type‐2 inflammation mediated by ILC2, eosinophilia and neutrophilia in the airway, and airway responsiveness in polygenic obese mice. Our findings indicate the potential for a new pharmacological therapeutic strategy to patients with asthma in the setting of obesity. Abbreviations: ICAM‐1, intercellular adhesion molecule 1; ILC2, group 2 innate lymphoid cells; GLP‐1RA, glucagon‐like peptide‐1 agonist

OBJECTIVES/HYPOTHESIS The objective of this study was to determine the role of thrombin-activatable fibrinolysis inhibitor (TAFI) as a candidate biomarker for therapeutic efficacy of sublingual immunotherapy (SLIT) and to identify the role of TAFI in the pathogenesis of allergic rhinitis (AR). STUDY DESIGN Retrospective cohort study and laboratory study. METHODS Serum was collected from patients with allergies to Japanese cedar pollen before, during, and after treatment with SLIT. We measured the levels of immunoreactive TAFI, C3a, and C5a in serum by enzyme-linked immunosorbent assay (ELISA) and assessed their relative impact on a combined symptom-medication score. We also examined the impact of TAFI on mast cells and fibroblasts in experiments performed in vitro. RESULTS Serum levels of TAFI increased significantly in response to SLIT. By contrast, serum C3a levels decreased significantly over time; we observed a significant negative correlation between serum levels of TAFI versus C3a and symptom-medication score. Mast cell degranulation was inhibited in response to TAFI, as it was the expression of both CCL11 and CCL5 in cultured fibroblasts. CONCLUSIONS High serum levels of TAFI may be induced by SLIT. TAFI may play a critical protective role in pathogenesis of AR by inactivating C3a and by inhibiting mast cell degranulation and chemokines expression in fibroblasts. LEVEL OF EVIDENCE 4 Laryngoscope, 131:2413-2420, 2021.

Interleukin (IL)-13-associated inflammatory response is important for the pathogenesis of allergic rhinitis (AR). Apremilast is a phosphodiesterase-4 (PDE4) inhibitor approved for psoriasis treatment. Here, we investigated the potential effects of Apremilast against IL-13-induced injury in human nasal epithelial cells (hNECs). Firstly, Apremilast ameliorated oxidative stress in IL-13-challenged cells by decreasing the levels of reactive oxygen species (ROS) and the production of malondialdehyde (MDA). Secondly, Apremilast inhibited the expressions of IL-6 and IL-8. Moreover, Apremilast inhibited the expressions of the chemokines colony-stimulating factor 2 (CSF2) and chemokine ligand 11 (CCL11). Interestingly, exposure to IL-13 increased the expressions of mucin 4 and mucin 5AC (MUC5AC), which was ameliorated by treatment with Apremilast. Interestingly, we found that Apremilast inhibited the phosphorylation of c-Jun-N-terminal kinase (JNK). Importantly, Apremilast reduced the levels of c-fos and c-Jun, the two AP-1 subfamilies. The luciferase reporter assay demonstrates that Apremilast reduced the transcriptional activity of activator protein 1 (AP-1). Lastly, we found that Apremilast prevented the activation of nuclear factor kappa-B (NF-κB) by decreasing the levels of nuclear NF-κB p65 and the luciferase activity of the NF-κB reporter. In summary, we conclude that Apremilast possesses a protective effect against IL-13-induced inflammatory response and mucin production in hNECs by inhibiting the activity of AP-1 and NF-κB.

Asthma is an important global health problem, and the main cause of asthma is allergic reaction and immune system dysregulation. Airway inflammation causes bronchial narrowing, and goblet cell hyperplasia leads to mucus hypersecretion that leads to airflow obstruction and difficulty breathing. The Th2 cytokines can induce allergic asthma. Camellia, Adhatoda, and Glycyrrhiza are the traditional medicines that are used in some countries. In the current study, we evaluated three herbal extracts on airway inflammatory responses in asthmatic mice. The asthma model was induced in mice that were divided into 6 groups: Phosphate-buffered saline (PBS) group, ovalbumin (OVA) group, OVA-budesonide group, OVA-Glycyrrhiza group, OVA-Camellia group, and OVA-Adhatoda group. Measurements of IL-4, IL-5, IL-13, glutamate oxaloacetate transaminase (GOT), glutamic pyruvic transaminase (GPT), IgE, histamine, percentages of eosinophils in bronchoalveolar lavage fluid (BALf), gene expression of COX-2, CCL24, CCL11, eotaxin, and histopathological study of lung were done. Adhatoda significantly attenuated the IL-4, IgE, and histamine levels. Glycyrrhiza attenuated the levels of IL-5, IL-13, GTP, GOT (on day 51), mRNA expression of eotaxin, CCL24, CCL11, and COX-2, eosinophil infiltration, mucus secretion, and goblet cell hyperplasia. Camellia decreased IL-13, GTP, COX-2 mRNA expression, mucus secretion, and goblet cell hyperplasia on day 31 and 51. We evaluated effect of three plants on allergic bio-factors. Glycyrrhiza as main anti-inflammatory treatment, Adhatoda as anti-allergic, and Camellia as anti-mucus releasing treatment can be used in attacks of allergic asthma.

Rhinovirus (RV) infections in asthmatic patients are often associated with asthma exacerbation, characterized by worsened airways hyperreactivity and increased immune cell infiltration to the airways. The C-X-C chemokines, CXCL3 and CXCL5, regulate neutrophil trafficking to the lung via CXCR2, and their expression in the asthmatic lung is associated with steroid-insensitive type 2 inflammatory signatures. Currently, the role of CXCL3 and CXCL5 in regulating neutrophilic and type 2 responses in viral-induced asthma exacerbation is unknown. Inhibition of CXCL3 or CXCL5 with silencing RNAs in a mouse model of RV-induced exacerbation of asthma attenuated the accumulation of CXCR2+ neutrophils, eosinophils, and innate lymphoid cells in the lung and decreased production of type 2 regulatory factors IL-25, IL-33, IL-5, IL-13, CCL11, and CCL24. Suppression of inflammation was associated with decreased airways hyperreactivity, mucus hypersecretion, and collagen deposition. Similar results were obtained by employing RC-3095, which has been shown to bind to CXCR2, or by depletion of neutrophils. Our data demonstrate that CXCL3 and CXCL5 may be critical in the perpetuation of RV-induced exacerbation of asthma through the recruitment of CXCR2-positive neutrophils and by promoting type 2 inflammation. Targeting the CXCL3/CXCL5/CXCR2 axis may provide a new therapeutic approach to attenuating RV-induced exacerbations of asthma.

Background Eosinophilic chronic rhinosinusitis (ECRS) is a chronic inflammatory disease, characterized by eosinophilic infiltration, T-helper type 2 (Th2-type) response, and olfactory dysfunction. A master regulator of Th2-type inflammation, thymic stromal lymphopoietin (TSLP), is important for basophil activation. TSLP-elicited basophils are a key factor in the pathogenesis of ECRS. Methods In order to elucidate the mechanisms of ECRS in humans, we aimed to establish a murine model of ECRS based on TSLP production in response to the topical application of MC903 (a vitamin D3 analog) and the subsequent TSLP-induced basophil activation. Histological analyses were performed to assess immune cell infiltration into the nasal mucosa and to explore the impact of eosinophilic inflammation on the olfactory epithelium. The status of Th2-type inflammation was evaluated by quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA). Results Eosinophils, basophils, and M2 macrophages increased significantly in the nasal mucosa of the mice treated with MC903 and ovalbumin (OVA), compared to those treated with OVA alone or the controls. Quantitative real-time PCR and ELISA revealed elevated expression of interleukin (IL)-4, IL-5, IL-13, TSLP, the chemokine CCL11, and CCL24 in the nasal mucosa of the ECRS mice. In parallel, thinned olfactory epithelium and decreased mature olfactory sensory neurons were observed in the ECRS mice. Conclusions Our model of ECRS displayed Th2-type inflammation in the sinonasal region, including both eosinophil infiltration and basophil infiltration. Additionally, olfactory epithelium turned out to be affected by eosinophilic inflammation. These features are consistent with the characteristics of the human ECRS.

Physiosomatic symptoms are an important part of schizophrenia phenomenology. The aim of this study is to examine the biomarker, neurocognitive and symptomatic correlates of physiosomatic symptoms in schizophrenia. We recruited 115 schizophrenia patients and 43 healthy controls and measured the Fibromyalgia and Chronic Fatigue Syndrome Rating (FF) scale, schizophrenia symptom dimensions, and the Brief Assessment of Cognition in Schizophrenia. We measured neuro-immune markers including plasma CCL11 (eotaxin), interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box 1 protein (HMGB1) and endogenous opioid system (EOS) markers including κ-opioid receptor (KOR), μ-opioid receptor (MOR), endomorphin-2 (EM2) and β-endorphin. Patients with an increased FF score display increased ratings of psychosis, hostility, excitement, formal though disorders, psycho-motor retardation and negative symptoms as compared with patients with lower FF scores. A large part of the variance in the FF score (55.1%) is explained by the regression on digit sequencing task, token motor task, list learning, IL-10, age (all inversely) and IL-6 (positively). Neural network analysis shows that the top-6 predictors of the FF score are (in descending order): IL-6, HMGB1, education, MOR, KOR and IL-10. We found that 45.1% of the variance in a latent vector extracted from cognitive test scores, schizophrenia symptoms and the FF score was explained by HMGB1, MOR, EM2, DKK1, and CCL11. Physiosomatic symptoms are an integral part of the phenome of schizophrenia. Neurotoxic immune pathways and lowered immune regulation coupled with alterations in the EOS appear to drive the physiosomatic symptoms of schizophrenia.

Background: Identification of clinically useful biomarkers for Nasal Polyposis in chronic rhinosinusitis (CRSwNP) has proven dif-ficult. We analyzed gene expression profiling data to find explanations for this. Methods: We analyzed mRNA expression profiling data, GSE36830, of six uncinate tissues from healthy controls and six NP from CRSwNP patients. We performed Ingenuity Pathway Analysis (IPA) of differentially expressed genes to identify pathways and predicted upstream regulators. Results: We identified 1,608 differentially expressed genes and 177 significant pathways, of which Th1 and Th2 activation pathway and leukocyte extravasation signaling were most significant. We identified 75 upstream regulators whose activity was predicted to be upregulated. These included regulators of known pathogenic and therapeutic relevance, like IL-4. However, only seven of the 75 regulators were actually differentially expressed in NP, namely CSF1, TYROBP, CCL2, CCL11, SELP, ADORA3, ICAM1. Interes-tingly, these did not include IL-4, and four of the seven were receptors. This suggested a potential explanation for the discrepancy between the predicted and observed expression levels of the regulators, namely that the receptors, and not their ligands, were upregulated. Indeed, we found that 10 receptors of key predicted upstream regulators were upregulated, including IL4R. Conclusion: Our findings indicate that the difficulties in finding specific biomarkers for CRSwNP depend on the complex underly-ing mechanisms, which include multiple pathways and regulators, each of which may be subdivided into multiple components such as ligands, soluble and membrane-bound receptors. This suggests that combinations of biomarkers may be needed for CRSwNP diagnostics.

International audience; Background: Interleukin-7 (IL-7) is the most important cytokine for T cell homeostasis. IL-7 signals through the IL-7 receptor (IL-7R) which is composed of an alpha chain (IL-7Rα), also called CD127 and a common gamma chain. T lymphocytes, especially T helper type 2, play a crucial role in the pathobiology of allergic asthma.Objective: To study the effects of an anti-CD127 monoclonal antibody (mAb) in a murine model of allergic airway inflammation induced by house dust mite (HDM).Methods: Allergic airway inflammation was induced in mice using a protocol comprising 4 weekly percutaneous sensitizations followed by 2 weekly intranasal challenges with total HDM extracts and treated by intraperitoneal injections of an anti-CD127 mAb. Because CD127 is shared by both IL-7R and the receptor for thymic stromal lymphopoietin (TSLP), a group of mice was also treated with an anti-IL-7 mAb to block only the IL-7 signaling pathway.Results: Anti-CD127 mAb-treated mice showed significantly lower airway resistance in response to methacholine and improvement in lung histology compared to isotype mAb-treated animals. Anti-CD127 mAb treatment significantly decreased the mRNA expression of Th2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL5/RANTES) in lung tissue, decreased the secretion of Th2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CXCL1 and CCL11/eotaxin) in bronchoalveolar lavage fluid (BALF), decreased serum HDM-specific IgE, and reduced the number of total leukocytes and leukocyte subpopulations such as eosinophils, macrophages, lymphocytes, T lymphocytes, and ILC2 in BALF and lung tissue. Mice treated with anti-IL-7 mAb also showed less allergic airway inflammation as evidenced by significantly lower airway resistance and fewer leukocytes in BALF and lung tissue compared to mice treated with the corresponding isotype control mAb.Conclusion and clinical relevance: Targeting the IL-7Rα by an anti-CD127 mAb improves allergic airway inflammation in mice and presents as a potential therapeutic approach for allergic asthma.

Chronic spontaneous urticaria (CSU) is considered to be primarily a mast cell–driven disease. However, recent evidence suggests that eosinophils may also have an axial role in symptomology. Histologic studies have demonstrated the presence of both eosinophils and eosinophil granules, indicative of activation, in CSU lesions. Although many allergic and inflammatory conditions are associated with a peripheral blood eosinophilia, the converse appears to be the case in CSU, with a peripheral blood eosinopenia being observed in many patients. Possible mechanisms include the depletion of blood eosinophils by recruitment into the skin during active disease and immunologic destruction in the blood. We also address in some detail the interactions between eosinophils and mast cells, particularly the cytokine cross-talk of these cells and mediator release possibly leading to clinical symptoms. Also, activation by eosinophil proteins of the coagulation pathway leads to the generation of thrombin and increased mast cell degranulation. Finally, treatments aimed at reducing eosinophil accumulation and activation, such as the anti–IL-5 antibodies mepolizumab, reslizumab, and benralizumab, have been reported to reduce CSU symptoms. Clearly, a new picture of an important role of eosinophils in the pathogenesis of CSU is emerging.

Berberine is an isoquinoline alkaloid isolated from various Chinese herbs that has potential of anti-inflammatory, anti-lipidemic, anti-neoplastic, and anti-diabetic activity. In this study, we evaluated the anti-inflammatory efficacy of berberine on allergic airway inflammation by targeting epithelial cells. Allergic airway inflammation driven by T helper 2 (Th2)-type immunity is characterized by airway hyperresponsiveness, elevated IgE production, and eosinophilic infiltration. For eosinophil recruitment, major chemoattractant CCL11 (eotaxin-1) was secreted by lung epithelial cells. BEAS-2B cells, a human bronchial epithelial cell line, were pre-treated with berberine and then activated by IL-4 plus TNF-α. The viability of BEAS-2B cells was assessed. Expression levels of IL-6 and CCL11 were determined using ELISA and real-time PCR. The signaling pathways of MAP kinases, NF-κB, and STAT6 were analyzed by western blot. Berberine treatment (≤1 μM) didn't significantly affect the viability of BEAS-2B cells with or without IL-4 plus TNF-stimulation. Berberine significantly inhibited the secretion of IL-6 and CCL11 from pro-inflammatory cytokine-activated BEAS-2B cells. NF-κB and MAP kinase pathways were seemingly unaffected in BEAS-2B cells with berberine treatment. Significant reduction of nuclear STAT6 protein expression in activated BEAS-2B cells with berberine treatment was observed. Current study reveals that berberine has inhibitory effect in pro-inflammatory cytokine-activated BEAS-2B cells through reducing IL-6 and CCL11 production, which is possibly modulated by suppressing STAT6 signaling pathway.

Pulp regeneration after transplantation of mobilized dental pulp stem cells (MDPSCs) declines in the aged dogs due in part to the chronic inflammation and/or cellular senescence. Eotaxin-1/C-C motif chemokine 11 (CCL11) is an inflammation marker via chemokine receptor 3 (CCR3). Moreover, CCR3 antagonist (CCR3A) can inhibit CCL11 binding to CCR3 and prevent CCL11/CCR3 signaling. The study aimed to examine the effect of CCR3A on cellular senescence and anti-inflammation/immunomodulation in human periodontal ligament cells (HPDLCs). The rejuvenating effects of CCR3A on neurite extension and migratory activity to promote pulp regeneration in aged dog teeth were also evaluated. In vivo, the amount of regenerated pulp tissues was significantly increased by transplantation of MDPSCs with CCR3A compared to control without CCR3A. In vitro, senescence of HPDLCs was induced after p-Cresol exposure, as indicated by increased cell size, decreased proliferation and increased senescence markers, p21 and IL-1β. Treatment of HPDLCs with CCR3A prevented the senescence effect of p-Cresol. Furthermore, CCR3A significantly decreased expression of CCL11, increased expression of immunomodulatory factor, IDO, and enhanced neurite extension and migratory activity. In conclusion, CCR3A protects against p-Cresol-induced cellular senescence and enhances rejuvenating effects, suggesting its potential utility to stimulate pulp regeneration in the aged teeth.

Targeting chemokine signaling is an attractive avenue for the treatment of inflammatory disorders. Tyrosine sulfation is an important post-translational modification (PTM) that enhances chemokine-receptor binding and is also utilized by a number of pathogenic organisms to improve the binding affinity of immune-suppressive chemokine binding proteins (CKBPs). Here we report the display selection of tyrosine-sulfated cyclic peptides using a reprogrammed genetic code to discover high-affinity ligands for the chemokine CCL11 (eotaxin-1). The selected cyclic sulfopeptides possess high affinity for the target chemokine (as well as one or more of the related family members CCL2, CCL7 and CCL24) and inhibit CCL11 activation of CC chemokine receptor 3 (CCR3). This work demonstrates the utility of exploiting native PTMs as binding motifs for the generation of new leads for medicinal chemistry.

Myocardial injury is a serious complication of sepsis. The present study aimed to identify potential biomarkers of sepsis-induced myocardial injury. Differentially expressed genes (DEGs) in patients and mice with sepsis-induced myocardial injury were identified via bioinformatic analysis. The identified DEG was tested in elderly patients with sepsis-induced myocardial injury. We identified 19 co-expressed DEGs. The most significant DEG was eotaxin-1/CCL11. We enrolled 25 controls without infections and 28 patients with sepsis-induced myocardial injury. Six of patients died within 30 days. Circulating eotaxin-1/CCL11 levels were significantly higher in patients with sepsis-induced myocardial injury than controls and were higher in non-survivors than survivors (both P < 0.01). Eotaxin-1/CCL11 was positively correlated with troponin I (r=0.48, P=0.01), B-type natriuretic peptide (BNP, r=0.44, P=0.02), and white blood cell (WBC) count (r=0.41, P=0.03). For the prediction of 30-day mortality, eotaxin-1/CCL11 had the greatest discriminatory ability (AUC 0.97) compared with troponin I (AUC 0.89), BNP (AUC 0.80), and WBC count (AUC 0.86). Taken together, eotaxin-1/CCL11 was upregulated in sepsis-injured myocardium and circulating eotaxin-1/CCL11 was a biomarker for predicting severity and mortality of elderly patients with sepsis-induced myocardial injury. These results suggest that eotaxin-1/CCL11 may become a useful biomarkers and potential therapeutic target for sepsis-induced myocardial injury.

A predominant protein of human eosinophils is galectin-10 (Gal-10), also known as Charcot-Leyden crystal protein (CLC-P) because of its remarkable ability to form Charcot-Leyden crystals (CLCs), which are frequently found in tissues from patients with eosinophilic disorders. CLC-P/Gal-10 is highly expressed in human eosinophils and considered a biomarker of eosinophil involvement in inflammation. However, the intracellular sites where large pools of CLC-P/Gal-10 constitutively reside are still unclear, and whether this protein is derived or not from eosinophil granules remains to be established. Here, we applied pre-embedding immunonanogold transmission electron microscopy combined with strategies for optimal antigen and cell preservation and quantitative imaging analysis to investigate, for the first time, the intracellular localization of CLC-P/Gal-10 at high resolution in resting and activated human eosinophils. We demonstrated that CLC-P/Gal-10 is mostly stored in the peripheral cytoplasm of human eosinophils, being accumulated within an area of ∼250 nm wide underneath the plasma membrane and not within specific (secretory) granules, a pattern also observed by immunofluorescence. High-resolution analysis of single cells revealed that CLC-P/Gal-10 interacts with the plasma membrane with immunoreactive microdomains of high CLC-P/Gal-10 density being found in ∼60% of the membrane area. Eosinophil stimulation with CCL11 or TNF-α, which are known inducers of eosinophil secretion, did not change the peripheral localization of CLC-P/Gal-10 as observed by both immunofluorescence and immuno-EM (electron microscopy). Thus, in contrast to other preformed eosinophil proteins, CLC-P/Gal-10 neither is stored within secretory granules nor exported through classical degranulation mechanisms (piecemeal degranulation and compound exocytosis).

Objective To characterize the CSF cytokine profile in chronic inflammatory demyelinating polyneuropathy (CIDP) patients with IgG4 anti‐neurofascin 155 (NF155) antibodies (NF155+ CIDP) or those lacking anti‐NF155 antibodies (NF155− CIDP). Methods Twenty‐eight CSF cytokines/chemokines/growth factors were measured by multiplexed fluorescent immunoassay in 35 patients with NF155+ CIDP, 36 with NF155− CIDP, and 28 with non‐inflammatory neurological disease (NIND). Results CSF CXCL8/IL‐8, IL‐13, TNF‐α, CCL11/eotaxin, CCL2/MCP‐1, and IFN‐γ were significantly higher, while IL‐1β, IL‐1ra, and G‐CSF were lower, in NF155+ CIDP than in NIND. Compared with NF155− CIDP, CXCL8/IL‐8 and IL‐13 were significantly higher, and IL‐1β, IL‐1ra, and IL‐6 were lower, in NF155+ CIDP. CXCL8/IL‐8, IL‐13, CCL11/eotaxin, CXCL10/IP‐10, CCL3/MIP‐1α, CCL4/MIP‐1β, and TNF‐α levels were positively correlated with markedly elevated CSF protein, while IL‐13, CCL11/eotaxin, and IL‐17 levels were positively correlated with increased CSF cell counts. IL‐13, CXCL8/IL‐8, CCL4/MIP‐1β, CCL3/MIP‐1α, and CCL5/RANTES were decreased by combined immunotherapies in nine NF155+ CIDP patients examined longitudinally. By contrast, NF155− CIDP had significantly increased IFN‐γ compared with NIND, and exhibited positive correlations of IFN‐γ, CXCL10/IP‐10, and CXCL8/IL‐8 with CSF protein. Canonical discriminant analysis of cytokines/chemokines revealed that NF155+ and NF155− CIDP were separable, and that IL‐4, IL‐10, and IL‐13 were the three most significant discriminators. Interpretation Intrathecal upregulation of type 2 helper T (Th2) cell cytokines is characteristic of IgG4 NF155+ CIDP, while type 1 helper T cell cytokines are increased in CIDP regardless of the presence or absence of anti‐NF155 antibodies, suggesting that overproduction of Th2 cell cytokines is unique to NF155+ CIDP.

Calprotectin is a heterodimer of the proteins S100A8 and S100A9, and it is an abundant innate immune protein associated with inflammation. In humans, calprotectin transcription and protein abundance are associated with asthma and disease severity. However, mechanistic studies in experimental asthma models have been inconclusive, identifying both protective and pathogenic effects of calprotectin. To clarify the role of calprotectin in asthma, calprotectin-deficient S100A9-/- and wild-type (WT) C57BL/6 mice were compared in a murine model of allergic airway inflammation. Mice were intranasally challenged with extracts of the clinically relevant allergen, Alternaria alternata (Alt Ext), or PBS every third day over 9 days. On Day 10, BAL fluid and lung tissue homogenates were harvested and allergic airway inflammation was assessed. Alt Ext challenge induced release of S100A8/S100A9 to the alveolar space and increased protein expression in the alveolar epithelium of WT mice. Compared with WT mice, S100A9-/- mice displayed significantly enhanced allergic airway inflammation, including production of IL-13, CCL11, CCL24, serum IgE, eosinophil recruitment, and airway resistance and elastance. In response to Alt Ext, S100A9-/- mice accumulated significantly more IL-13+IL-5+CD4+ T-helper type 2 cells. S100A9-/- mice also accumulated a significantly lower proportion of CD4+ T regulatory (Treg) cells in the lung that had significantly lower expression of CD25. Calprotectin enhanced WT Treg cell suppressive activity in vitro. Therefore, this study identifies a role for the innate immune protein, S100A9, in protection from CD4+ T-helper type 2 cell hyperinflammation in response to Alt Ext. This protection is mediated, at least in part, by CD4+ Treg cell function.

SummaryVaccinations against SARS-CoV-2 are effective in COVID-19. However, with limited vaccine access, vaccine hesitancy and variant breakthroughs, there is still a need for effective and safe early treatments. Two community-based clinical trials of the inhaled corticosteroid, budesonide, have recently been published showing and improvement in patients with COVID-19 treated early with budesonide1,2. To understand mechanistically how budesonide was beneficial, inflammatory mediators were assessed in the nasal mucosa of patients recruited to the Steroids in COVID (STOIC1) trial and a cohort of SARS-CoV-2 negative individuals. Here we show that in early COVID-19, elevation in viral response proteins and Th1 and Th2 inflammation occurs. Longitudinal sampling in the natural course of COVID-19 showed persistently high interferon levels and elevated concentrations of the eosinophil chemokine, CCL11. In patients who deteriorate, the initial nasal mucosal signal is characterised by a marked suppression of the early inflammatory response, with reduced concentrations of interferon and inflammatory cytokines, but elevated eosinophil chemokines. Systemic inflammation remained altered in COVID-19 patients, implying that even after symptom resolution, changes in immunological mediators do not resolve. Budesonide treatment decreased IL-33 and IFN-γ, implying a reduction in epithelial damage and dampening of the interferon response. Budesonide treatment also increased CCL17 concentrations, suggesting an improved T-cell response; and significantly alters inflammatory pathways giving further insight into how this treatment can accelerate patient recovery.Abstract Figure

Background: Orthodontic appliances elicit the secretions of some cytokines, chemokines, and growth factors which further have some significances in the remodeling of periodontium tissues. The significant differential forces applied on the periodontium by different types of orthodontic appliances. The secretion of these factors is indirectly responsible for the proper resorption of bones of the periodontal region through molecular signaling, which further supports to facilitate organized movement of the teeth. Objective: In the present study, we carried out the assessment and comparative analysis of the growth factors and chemokines present in the saliva samples of the human subjects of orthodontic treatment with two different treatment modalities: conventional lingual and labial fixed orthodontic appliances. Materials and Methods: Total 40 saliva samples were collected of which 20 subjects were treated with the conventional lingual appliances and 20 subjects with the labial fixed appliances. All the salivary samples were acquired from the subjects after 21 days treatment. Cytometric bead array was performed to assess the growth factors and chemokines in the saliva on the flow cytometer. Results: No significant differences were seen in the growth factor secretion in the saliva of both types of subjects. The same trend was observed for the chemokine secretion in the saliva except CXCL8, CCL11, CCL2, CCL5, and CXCL9. Conclusion: The similarity in chemokine and growth factor profile between labial and lingual fixed orthodontic appliances indicates that their molecular mechanisms and overall effect on the periodontium are analogous.

Background: Postoperative cognitive dysfunction is widely recognized as severe postoperative central nervous dysfunction and has a significant impact on the ’patient’s physical and mental health. Methods: Postoperative models of tibial fracture in aged rats were established, including the control group, model group, CCL11 protein injection group, and saline injection group. Morris water maze test was used to detect the behavioral characteristics of rats. Enzyme-Linked Immunosorbent Assay was used or determine the content of CCL11 and CXCL10. Immunofluorescence staining was used to detect the distribution of CD14+CD163+macro-phages in colon tissues and CD11b+CCR3+microglia cells in hippocampal tissues. Western blot analyzed NOX1 and STAT3 expression in hippocampus tissues. Results: Water maze test results confirmed severe cognitive impairment in CCL11 rats. The content of CCL11 and CXCL10 in the CCL11 group was much higher than that of the model group. The distribution of macrophage and microglia cells in the CCL11 model group was greater than that in the model group and the saline group. The expression of NOX1 and STAT3 in the CCL11 group was higher compared with the model group. Conclusion: Abnormal macrophage function and excessive CCL11 secretion were observed in the rats with lower limb fractures after surgery. Postoperative central inflammation in rats with lower limb fracture induced postoperative cognitive dysfunction through the gut-brain axis molecular mechanism.

Introdução: Avaliar a associação entre níveis plasmáticos da quimiocina CCL11, coeficiente de inteligência e prática da amamentação em homens com esquizofrenia em condições psiquiátricas estáveis sob acompanhamento ambulatorial em um serviço de saúde pública. Métodos: Foi realizado estudo caso-controle com 60 indivíduos: 30 pacientes com esquizofrenia e 30 controles saudáveis, dos quais 15 de cada grupo foram expostos ao aleitamento materno e 15 não foram. Foi aplicado questionário abordando questões socioeconômicas, história ao nascer, dados clínicos e alimentação ao nascer. Foi dosada a quimiocina CCL11 e aplicados testes psicológicos para avaliar quociente de inteligência, funcionalidade, sintomas psiquiátricos, curso da doença e diagnóstico. Para os controles, foi utilizada uma escala para descartar doença psiquiátrica. Resultados: A quimiocina CCL11 apresentou valores significativamente mais altos (> 0,5) em pacientes com esquizofrenia quando comparados aos controles. No grupo de amamentados, os esquizofrênicos apresentaram valores significativamente mais altos a nível intermediário (entre 0.106 e 0.5). Não houve correlação da CCL11 com o número de hospitalizações, idade, tempo de diagnóstico e escolaridade. Não foi evidenciada correlação entre tempo de aleitamento materno em relação aos fatores do Brief Psychiatric Rating Scale. Houve uma tendência de correlação entre a idade de início da doença e o aleitamento materno. Foi encontrada correlação positiva do CCL11 com o tempo de aleitamento materno. Ao comparar os pacientes esquizofrênicos que foram aleitados com os que não foram, foi encontrada diferença estatisticamente significativa apenas para o quociente de inteligência. Conclusão: O aleitamento materno está associado a níveis mais baixos de CCL11, escores mais altos de quociente de inteligência e a esquizofrenia. A quimiocina CCL11 é mais alta em quem não amamentou, especialmente nos esquizofrênicos. Introduction: To evaluate the association between plasma levels of chemokine CCL11, intelligence quotient, and exposure to breastfeeding in men with schizophrenia under stable psychiatric condition and monitored as outpatients in a public health care unit. Methods: A case-control study of 60 individuals, 30 patients with schizophrenia and 30 healthy controls; in each group, 15 were exposed to breastfeeding and 15 were not. A questionnaire addressing socioeconomic issues, history at birth, clinical data, and feeding at birth was administered. Chemokine CCL11 levels were measured, and psychological tests were applied to assess intelligence quotient, functional status, psychiatric symptoms, disease course, and diagnosis. A scale to rule psychiatric illness was used for the controls. Results: Chemokine CCL11 levels were significantly higher (> 0.5) in patients with schizophrenia than in controls. In the breastfed group, patients with schizophrenia also had significantly higher CCL11 levels, but at an intermediate level (between 0.106 and 0.5). There was no correlation between CCL11 and number of hospitalizations, age, time since diagnosis, or level of education, nor between duration of breastfeeding and the Brief Psychiatric Rating Scale factors. A trend toward a correlation was observed between age at disease onset and breastfeeding. There was a positive correlation between CCL11 and duration of breastfeeding. The comparison of patients with schizophrenia who were breastfed vs those who were not breastfed showed a statistically significant difference only in intelligence quotient. Conclusion: Breastfeeding is associated with lower CCL11 levels, higher intelligence quotient scores, and schizophrenia. Chemokine CCL11 levels are higher in those not exposed to breastfeeding, especially in patients with schizophrenia.

Although exposure to ambient particulate matter (PM) is linked to asthma, the health effects of co-existing vapor-phase organic pollutants (vapor) and their combined effects with PM on this disease are poorly understood. We used a murine asthma model to test the hypothesis that exposure to vapor would enhance allergic sensitization and this effect would be further strengthened by co-existing PM. We found that vapor and PM each individually exerted adjuvant effects on OVA sensitization. Co-exposure to vapor and PM during sensitization further enhanced allergic lung inflammation and OVA-specific antibody production which was accompanied by pulmonary cytokine/chemokine milieu that favored T-helper 2 immunity (i.e. increased IL-4, downregulation of Il12a and Ifng, and upregulation of Ccl11 and Ccl8). TNFa, IL-6, Ccl12, Cxcl1 and detoxification/antioxidant enzyme responses in the lung were pollutant-dependent. Inhibition of lipopolysaccharide-induced IL-12 secretion from primary antigen-presenting dendritic cells correlated positively with vapor’s oxidant potential. In conclusion, concurrent exposure to vapor and PM led to significantly exaggerated adjuvant effects on allergic lung inflammation which were more potent than that of each pollutant type alone. These findings suggest that the effects of multi-component air pollution on asthma may be significantly underestimated if research only focuses on a single air pollutant (e.g., PM).

Ulcerative colitis (UC) is a complex inflammatory bowel disorder that can induce colonic and rectal dysfunction. Mesalazine, a first-line medicine, is routinely prescribed for UC treatment. However, the pharmacological targets of mesalazine against UC are not detailed in current publications. In the current study, a transcriptomics strategy was applied to reveal the therapeutic targets and molecular mechanisms of mesalazine for treating dextran sulfate sodium (DSS)-induced UC in mice. Compared with the UC group, a total of 1,663 differentially expressed genes were identified in mesalazine-treated mice, of which 262 were upregulated and 1,401 were downregulated. GO and KEGG enrichment analyses indicated that the protective actions of mesalazine for treating UC were related to the functional regulation of immune inflammatory response, such as the regulation of T cells, white blood cells, and cytokine receptor pathways. In addition, ingenuity pathway analysis of the gene network further revealed the inhibitory action of mesalazine on C–C motif chemokine ligands (CCL11 and CCL21) and C–X–C motif chemokine ligands (CXCL3 and CXCR2). Taken together, the current transcriptomic findings revealed anti-UC pharmacological targets, including the newly discovered biotargets CCL11, CCL21, CXCL3, and CXCR2, of mesalazine against DSS-induced intestinal inflammation.

Meibomian gland dysfunction (MGD) has become a prevalent ocular surface disorder. Its pathogenesis is regarded as a self-perpetuating inflammatory vicious circle. Intense Pulsed Light (IPL) treatment was recently applied to improve the meibomian gland function and reduce symptoms of MGD. However, studies investigating the change of specific inflammatory cytokines during IPL treatment remained sparse. To further figure out how IPL treatment modulates the inflammatory cytokines in tears of MGD, we therefore performed a cross-sectional study and enrolled 32 patients from March 2019 to December 2020. The patients received 3 sessions of IPL treatment (10 to 16 J/cm2) at 4-week interval. The signs and symptoms of MGD were evaluated by ocular surface disease index (OSDI), tear film breakup time (TBUT), and meibomian gland yield secretion score (MGYSS). The clinical evaluators and tear samples were analyzed at baseline and at each IPL treatment session. Concentrations of (chemokine ligand) CXCL1, (C-C motif chemokine) CCL11, (tumor necrosis factor) TNF-α, (interferon) IFN-γ, (interleukin) IL-2, IL-6 and (tissue inhibitor of metalloproteinase) TIMP-1were measured by Quantibody Human Dry Eye Disease Array1. OSDI significantly decreased after IPL treatment compared with baseline. TBUT and MGYSS increased consecutively during treatment. CXCL1, CCL11, TNF-α, IFN-γ, IL-2, IL-6 presented significantly decrease and TIMP-1 showed significantly increase from the pretreatment baseline. The changed concentrations of TNF-α, IFN-γ, IL-2, TIMP-1 correlated with TBUT, the changed values of CXCL1, TNF-α, IFN-γ, CCL11, IL-2, IL-6, TIMP-1 correlated with MGYSS, and the changed concentrations of CXCL1, IFN-γ, CCL11, IL-2, IL-6 correlated with TIMP-1. The data supported IPL treatment could significantly relieve both signs and symptoms of MGD. The therapeutic effect of IPL treatment may originate from regulation of inflammatory cytokines including CXCL1, TNF-α, IFN-γ, CCL11, IL-2, IL-6, and TIMP-1.

BackgroundChronic obstructive pulmonary disease (COPD) is associated with increased risk of severe COVID-19, but the mechanisms are unclear. Besides, patients with severe COVID-19 have been reported to have increased levels of several immune mediators.MethodsNinety-two proteins were quantified in 315 plasma samples from 118 asthmatics, 99 COPD patients and 98 healthy controls (age 40-90 years), who were recruited in Colombia before the COVID-19 pandemic. Protein levels were compared between each disease group and healthy controls. Significant proteins were compared to the gene signatures of SARS-CoV-2 infection reported in the “COVID-19 Drug and Gene Set Library” and with experimentally tested protein biomarkers of severe COVID-19.ResultsForty-one plasma proteins showed differences between patients and controls. Asthmatic patients have increased levels in IL-6 while COPD patients have a broader systemic inflammatory dysregulation driven by HGF, OPG, and several chemokines (CXCL9, CXCL10, CXCL11, CX3CL1, CXCL1, MCP-3, MCP-4, CCL3, CCL4 and CCL11). These proteins are involved in chemokine signaling pathways related with response to viral infections and some, were found up-regulated upon SARS-CoV-2 experimental infection of Calu-3 cells as reported in the COVID-19 Related Gene Sets database. An increase of HPG, CXCL9, CXCL10, IL-6, MCP-3, TNF and EN-RAGE has also been experimentally detected in patients with severe COVID-19.ConclusionsCOPD patients have altered levels of plasma proteins that have been reported increased in patients with severe COVID-19. Our study suggests that COPD patients have a systemic dysregulation in chemokine networks (including HGF and CXCL9) that could make them more susceptible to severe COVID-19. Also, that IL-6 levels are increased in some asthmatic patients (especially in females) and this may influence their response to COVID-19. The findings in this study depict a novel panel of inflammatory plasma proteins in COPD patients that may potentially associate with increased susceptibility to severe COVID-19 and might be useful as a biomarker signature after future experimental validation.

The parasitic nematode Trichinella spiralis causes trichinellosis, a serious food-borne parasitic zoonosis worldwide. Infection with T. spiralis may also cause myocarditis. In the present study, we used mouse models to assess the impact of blockage of galectin-receptor interactions by α-lactose on cardiac immunopathology during acute T. spiralis experimental infection. Our data demonstrated that, after T. spiralis infection, blockage of galectin-receptor interactions resulted in cardiac dysfunction detected by transthoracic conventional echocardiography, and increased serum Gal-3 level, a biomarker of myocardial damage. In addition, there were increased eosinophil number in peripheral blood, and increased eosinophil infiltration in the heart and spleen tissues accompanied with increased mRNA levels of eosinophil granule proteins (including eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO)) and IL-5 in these organs; increased cardiac fibrosis accompanied with increased Gal-3 and collagen 1 expressions in the hearts of mice with blockage of galectin-receptor interactions after T. spiralis infection. Correlation analysis showed that significant positive correlations existed between the mRNA levels of Gal-3 and ECP/EPO/eosinophil major basic protein/IL-5/CCL11/CCR3/α-SMA/collagen 1 in the hearts of both T. spiralis-infected mice and T. spiralis-infected mice with blockage of galectin-receptor interactions. Our data suggest that galectin-receptor interactions play a pivotal role during acute T. spiralis infection, and lack of galectin-receptor interactions upregulates Gal-3 which, in turn, leads to elevated heart eosinophil recruitment, exacerbated heart pathology and fibrosis, and heart functional damage.

Alcohol is known to modulate the immune system. Neuroinflammatory cytokine dysregulation plays an essential role in the pathophysiology of alcohol dependence (AD). Preclinical studies have indicated that alcohol consumption upregulates the pro-inflammatory cytokine CC motif ligand 11 (CCL11, also known as eotaxin-1). We examined CCL11 levels in patients with AD and in mice administered alcohol.The plasma CCL11 levels of 151 patients with AD and 116 healthy controls were measured. In addition, we followed the CCL11 levels, alcohol cravings and psychological symptoms in patients with AD after 1 and 2 weeks of detoxification. Furthermore, we examined CCL11 changes in mice administered alcohol for 5 days.CCL11 levels were higher in patients with AD than in controls and declined during detoxification. CCL11 levels were positively correlated with AD severity (p 0.001). Furthermore, mice exposed to alcohol exhibited a higher CCL11 level. The receiver operating characteristic curve revealed that a CCL11 level of 72.5 pg/mL could significantly differentiate patients with AD from controls (area under the curve: 0.77; p 0.001). Reductions in CCL11 levels during detoxification were correlated with reductions in alcohol craving, depression, and anxiety.Our data from humans and mice suggest that chronic alcohol consumption is associated with an increase in CCL11 levels. CCL11 levels are correlated with AD severity and may be a potential indicator of AD. The CCL11 reduction after alcohol discontinuation is associated with alleviation of clinical symptoms. Collectively, our findings suggest that CCL11 is involved in the neurobiological mechanisms underlying AD.