36 results on '"Meisel, Marlies"'
Search Results
2. Melanoma and microbiota: Current understanding and future directions
- Author
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Routy, Bertrand, Jackson, Tanisha, Mählmann, Laura, Baumgartner, Christina K., Blaser, Martin, Byrd, Allyson, Corvaia, Nathalie, Couts, Kasey, Davar, Diwakar, Derosa, Lisa, Hang, Howard C., Hospers, Geke, Isaksen, Morten, Kroemer, Guido, Malard, Florent, McCoy, Kathy D., Meisel, Marlies, Pal, Sumanta, Ronai, Ze’ev, Segal, Eran, Sepich-Poore, Gregory D., Shaikh, Fyza, Sweis, Randy F., Trinchieri, Giorgio, van den Brink, Marcel, Weersma, Rinse K., Whiteson, Katrine, Zhao, Liping, McQuade, Jennifer, Zarour, Hassane, and Zitvogel, Laurence
- Published
- 2024
- Full Text
- View/download PDF
3. The gut protist Tritrichomonas arnold restrains virus-mediated loss of oral tolerance by modulating dietary antigen-presenting dendritic cells
- Author
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Medina Sanchez, Luzmariel, Siller, Magdalena, Zeng, Yanlin, Brigleb, Pamela H., Sangani, Kishan A., Soto, Ariadna S., Engl, Clarisse, Laughlin, Colin R., Rana, Mohit, Van Der Kraak, Lauren, Pandey, Surya P., Bender, Mackenzie J., Fitzgerald, Britney, Hedden, Lee, Fiske, Kay, Taylor, Gwen M., Wright, Austin P., Mehta, Isha D., Rahman, Syed A., Galipeau, Heather J., Mullett, Steven J., Gelhaus, Stacy L., Watkins, Simon C., Bercik, Premysl, Nice, Timothy J., Jabri, Bana, Meisel, Marlies, Das, Jishnu, Dermody, Terence S., Verdú, Elena F., and Hinterleitner, Reinhard
- Published
- 2023
- Full Text
- View/download PDF
4. Systemic Immunoregulatory Consequences of Gut Commensal Translocation
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McPherson, Alex C., Pandey, Surya P., Bender, Mackenzie J., and Meisel, Marlies
- Published
- 2021
- Full Text
- View/download PDF
5. Mechanisms by which gut microorganisms influence food sensitivities
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Caminero, Alberto, Meisel, Marlies, Jabri, Bana, and Verdu, Elena F.
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- 2019
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6. Natural polyreactive IgA antibodies coat the intestinal microbiota
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Bunker, Jeffrey J., Erickson, Steven A., Flynn, Theodore M., Henry, Carole, Koval, Jason C., Meisel, Marlies, Jabri, Bana, Antonopoulos, Dionysios A., Wilson, Patrick C., and Bendelac, Albert
- Published
- 2017
7. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease
- Author
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Bouziat, Romain, Hinterleitner, Reinhard, Brown, Judy J., Stencel-Baerenwald, Jennifer E., Ikizler, Mine, Mayassi, Toufic, Meisel, Marlies, Kim, Sangman M., Discepolo, Valentina, Pruijssers, Andrea J., Ernest, Jordan D., Iskarpatyoti, Jason A., Costes, Léa M. M., Lawrence, Ian, Palanski, Brad A., Varma, Mukund, Zurenski, Matthew A., Khomandiak, Solomiia, McAllister, Nicole, Aravamudhan, Pavithra, Boehme, Karl W., Hu, Fengling, Samsom, Janneke N., Reinecker, Hans-Christian, Kupfer, Sonia S., Guandalini, Stefano, Semrad, Carol E., Abadie, Valérie, Khosla, Chaitan, Barreiro, Luis B., Xavier, Ramnik J., Ng, Aylwin, Dermody, Terence S., and Jabri, Bana
- Published
- 2017
8. Altered hepatic and intestinal homeostasis in a neonatal murine model of shortterm total parenteral nutrition and antibiotics.
- Author
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Mims, Tahliyah S., Kumari, Roshan, Leathem, Cameron, Antunes, Karen, Joseph, Sydney, Mei-I Yen, Ferstl, Danielle, Jamieson, Sophia M., Sabbar, Austin, Biebel, Claudia, Lazarevic, Nikolai, Willis, Nathaniel B., Henry, Lydia, Chi-Liang E. Yen, Smith, Joseph P., Gosain, Ankush, Meisel, Marlies, Willis, Kent A., Talati, Ajay J., and Elabiad, Mohammad. T.
- Subjects
PARENTERAL feeding ,REGULATOR genes ,INFANT weaning ,ANTIBIOTICS ,INTESTINES ,COLONY-forming units assay ,LIVER histology - Abstract
Parenteral nutrition (PN) prevents starvation and supports metabolic requirements intravenously when patients are unable to be fed enterally. Clinically, infants are frequently provided PN in intensive care settings along with exposure to antibiotics (ABX) to minimize infection during care. Unfortunately, neonates experience extremely high rates of hepatic complications. Adult rodent and piglet models of PN are well-established but neonatal models capable of leveraging the considerable transgenic potential of the mouse remain underdeveloped. Utilizing our newly established neonatal murine PN mouse model, we administered ABX or controlled drinking water to timed pregnant dams to disrupt the maternal microbiome. We randomized mouse pups to PN or sham surgery controls +/- ABX exposure. ABX or short-term PN decreased liver and brain organ weights, intestinal length, and mucosal architecture (vs. controls). PN significantly elevated evidence of hepatic proinflammatory markers, neutrophils and macrophage counts, bacterial colony-forming units, and evidence of cholestasis risk, which was blocked by ABX. However, ABX uniquely elevated metabolic regulatory genes resulting in accumulation of hepatocyte lipids, triglycerides, and elevated tauro-chenoxycholic acid (TCDCA) in serum. Within the gut, PN elevated the relative abundance of Akkermansia, Enterococcus, and Suterella with decreased Anaerostipes and Lactobacillus compared with controls, whereas ABX enriched Proteobacteria. We conclude that short-term PN elevates hepatic inflammatory stress and risk of cholestasis in early life. Although concurrent ABX exposure protects against hepatic immune activation during PN, the dual exposure modulates metabolism and may contribute toward early steatosis phenotype, sometimes observed in infants unable to wean from PN. NEW & NOTEWORTHY This study successfully established a translationally relevant, murine neonatal parenteral nutrition (PN) model. Short-term PN is sufficient to induce hepatitis-associated cholestasis in a neonatal murine model that can be used to understand disease in early life. The administration of antibiotics during PN protects animals from bacterial translocation and proinflammatory responses but induces unique metabolic shifts that may predispose the liver toward early steatosis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
9. Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host
- Author
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Meisel, Marlies, Hinterleitner, Reinhard, Pacis, Alain, Chen, Li, Earley, Zachary M., Mayassi, Toufic, and Pierre, Joseph F.
- Subjects
Gene mutation -- Health aspects ,Hematopoietic stem cells -- Health aspects ,Leukemia -- Development and progression -- Genetic aspects ,Stem cells ,Enzymes ,Epigenetic inheritance ,Interleukins ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Somatic mutations in tet methylcytosinedioxygenase 2 (TET2), which encodes an epigenetic modifier enzyme, drive the development of haematopoietic malignancies.sup.1-7. In both humans and mice, TET2 deficiency leads to increased self-renewal of haematopoietic stem cells with a net developmental bias towards the myeloid lineage.sup.1,4,8,9. However, pre-leukaemic myeloproliferation (PMP) occurs in only a fraction of Tet2.sup.-/- mice.sup.8,9 and humans with TET2 mutations.sup.1,3,5-7, suggesting that extrinsic non-cell-autonomous factors are required for disease onset. Here we show that bacterial translocation and increased interleukin-6 production, resulting from dysfunction of the small-intestinal barrier, are critical for the development of PMP in mice that lack Tet2 expression in haematopoietic cells. Furthermore, in symptom-free Tet2.sup.-/- mice, PMP can be induced by disrupting intestinal barrier integrity, or in response to systemic bacterial stimuli such as the toll-like receptor 2 agonist. PMP was reversed by antibiotic treatment and failed to develop in germ-free Tet2.sup.-/- mice, which illustrates the importance of microbial signals in the development of this condition. Our findings demonstrate the requirement for microbial-dependent inflammation in the development of PMP and provide a mechanistic basis for the variation in PMP penetrance observed in Tet2.sup.-/- mice. This study will prompt new lines of investigation that may profoundly affect the prevention and management of haematopoietic malignancies.Microbial signals are crucial to the development of pre-leukaemic myeloproliferation, which can be induced by disrupting the intestinal barrier or by introducing systemic bacterial stimuli in Tet2-deficient mice., Author(s): Marlies Meisel [sup.1] [sup.2] , Reinhard Hinterleitner [sup.1] [sup.2] , Alain Pacis [sup.3] [sup.4] , Li Chen [sup.1] [sup.2] , Zachary M. Earley [sup.1] [sup.2] , Toufic Mayassi [sup.1] [...]
- Published
- 2018
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- View/download PDF
10. Intestinal Microbiota Modulates Gluten-Induced Immunopathology in Humanized Mice
- Author
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Galipeau, Heather J., McCarville, Justin L., Huebener, Sina, Litwin, Owen, Meisel, Marlies, Jabri, Bana, Sanz, Yolanda, Murray, Joseph A., Jordana, Manel, Alaedini, Armin, Chirdo, Fernando G., and Verdu, Elena F.
- Published
- 2015
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11. Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2
- Author
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Caminero, Alberto, McCarville, Justin L., Galipeau, Heather J., Deraison, Celine, Bernier, Steve P., Constante, Marco, Rolland, Corinne, Meisel, Marlies, Murray, Joseph A., Yu, Xuechen B., Alaedini, Armin, Coombes, Brian K., Bercik, Premysl, Southward, Carolyn M., Ruf, Wolfram, Jabri, Bana, Chirdo, Fernando G., Casqueiro, Javier, Surette, Michael G., Vergnolle, Nathalie, and Verdu, Elena F.
- Published
- 2019
- Full Text
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12. The microbiota control the neonatal WNT-ernet.
- Author
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McPherson, Alex C. and Meisel, Marlies
- Subjects
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STEM cells , *MACROPHAGES - Abstract
The microbiome plays a fundamental role in maintaining intestinal stem cell (ISC)-niche equilibrium. In this issue of Immunity , Kim and colleagues uncover a mechanism by which the microbiota drives macrophage WNT ligand-release to maintain ISC-niche homeostasis during early postnatal development. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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- View/download PDF
13. Well-trained, healthy triathletes experience no adverse health risks regarding oxidative stress and DNA damage by participating in an ultra-endurance event
- Author
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Wagner, Karl-Heinz, Reichhold, Stefanie, Hölzl, Christine, Knasmüller, Siegfried, Nics, Lukas, Meisel, Marlies, and Neubauer, Oliver
- Published
- 2010
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14. Innate and Adaptive Humoral Responses Coat Distinct Commensal Bacteria with Immunoglobulin A
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Bunker, Jeffrey J., Flynn, Theodore M., Koval, Jason C., Shaw, Dustin G., Meisel, Marlies, McDonald, Benjamin D., Ishizuka, Isabel E., Dent, Alexander L., Wilson, Patrick C., Jabri, Bana, Antonopoulos, Dionysios A., and Bendelac, Albert
- Published
- 2015
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15. Adenovirus-vectored SARS-CoV-2 vaccine expressing S1-N fusion protein.
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Khan, Muhammad S, Kim, Eun, McPherson, Alex, Weisel, Florian J, Huang, Shaohua, Kenniston, Thomas W, Percivalle, Elena, Cassaniti, Irene, Baldanti, Fausto, Meisel, Marlies, and Gambotto, Andrea
- Published
- 2022
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16. Cbl-b mediates TGFβ sensitivity by downregulating inhibitory SMAD7 in primary T cells
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Gruber, Thomas, Hinterleitner, Reinhard, Hermann-Kleiter, Natascha, Meisel, Marlies, Kleiter, Ingo, Wang, Chiuhui Mary, Viola, Antonella, Pfeifhofer-Obermair, Christa, and Baier, Gottfried
- Published
- 2013
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17. The Kinase PKCα Selectively Upregulates Interleukin-17A during Th17 Cell Immune Responses
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Meisel, Marlies, Hermann-Kleiter, Natascha, Hinterleitner, Reinhard, Gruber, Thomas, Wachowicz, Katarzyna, Pfeifhofer-Obermair, Christa, Fresser, Friedrich, Leitges, Michael, Soldani, Cristiana, Viola, Antonella, Kaminski, Sandra, and Baier, Gottfried
- Published
- 2013
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18. Team victory, yellow helmets for a computational tour de force.
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Phelps, Catherine M. and Meisel, Marlies
- Subjects
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HELMETS , *GUT microbiome , *MULTIPLE sclerosis , *TEAMS - Abstract
Changes in the gut microbiota are associated with the etiopathogenesis of complex diseases, such as multiple sclerosis. In this issue of Cell , the international Multiple Sclerosis Microbiome Study consortium deployed a multi-omics approach to profile the composition and function of the gut microbiome in an extensive cohort of MS patients. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
19. Microbes and metabolites in immunity.
- Author
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Elinav, Eran, Devkota, Suzanne, Meisel, Marlies, Zhu, Shu, Chu, Hiutung, Chen, Haiwei, Puschhof, Jens, McAllister, Florencia, Platt, Randall Jeffrey, and Honda, Kenya
- Subjects
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IMMUNE system , *METABOLITES , *IMMUNITY , *MICROORGANISMS - Abstract
The immune system has a vital, albeit complex, relationship with the microbes residing within us, one that we are only beginning to understand. We asked investigators what they felt were the fundamental challenges we currently face in unraveling the impacts of microbes and their metabolites on host immunity and to discuss key opportunities toward achieving future insights and innovation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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- View/download PDF
20. 545 Microbiota From an Active Celiac Donor Modulates Intraepithelial Lymphocyte Numbers and Phenotype in the Mouse Small Intestine
- Author
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McCarville, Justin, Meisel, Marlies, Galipeau, Heather J., Lau, Jennifer, Surette, Michael, Sanz, Yolanda, Jabri, Bana, and Verdu, Elena F.
- Published
- 2016
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21. Protein Kinase C θ Regulates the Phenotype of Murine CD4+ Th17 Cells.
- Author
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Wachowicz, Katarzyna, Hermann-Kleiter, Natascha, Meisel, Marlies, Siegmund, Kerstin, Thuille, Nikolaus, and Baier, Gottfried
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INFLAMMATION ,PROTEIN kinase C ,PHENOTYPES ,LABORATORY mice ,CELLULAR signal transduction ,T cell receptors ,ANTIGEN receptors - Abstract
Protein kinase C θ (PKCθ) is involved in signaling downstream of the T cell antigen receptor (TCR) and is important for shaping effector T cell functions and inflammatory disease development. Acquisition of Th1-like effector features by Th17 cells has been linked to increased pathogenic potential. However, the molecular mechanisms underlying Th17/Th1 phenotypic instability remain largely unknown. In the current study, we address the role of PKCθ in differentiation and function of Th17 cells by using genetic knock-out mice. Implementing in vitro (polarizing T cell cultures) and in vivo (experimental autoimmune encephalomyelitis model, EAE) techniques, we demonstrated that PKCθ-deficient CD4
+ T cells show normal Th17 marker gene expression (interleukin 17A/F, RORγt), accompanied by enhanced production of the Th1-typical markers such as interferon gamma (IFN-γ) and transcription factor T-bet. Mechanistically, this phenotype was linked to aberrantly elevated Stat4 mRNA levels in PKCθ−/− CD4+ T cells during the priming phase of Th17 differentiation. In contrast, transcription of the Stat4 gene was suppressed in Th17-primed wild-type cells. This change in cellular effector phenotype was reflected in vivo by prolonged neurological impairment of PKCθ-deficient mice during the course of EAE. Taken together, our data provide genetic evidence that PKCθ is critical for stabilizing Th17 cell phenotype by selective suppression of the STAT4/IFN-γ/T-bet axis at the onset of differentiation. [ABSTRACT FROM AUTHOR]- Published
- 2014
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22. Nuclear orphan receptor NR2F6 directly antagonizes NFAT and RORγt binding to the Il17a promoter
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Hermann-Kleiter, Natascha, Meisel, Marlies, Fresser, Friedrich, Thuille, Nikolaus, Müller, Mathias, Roth, Lukas, Katopodis, Andreas, and Baier, Gottfried
- Subjects
- *
NFAT5 protein , *INTERLEUKINS , *CYTOKINES , *DNA , *HEREDITY , *PROTEIN binding , *PROMOTERS (Genetics) - Abstract
Abstract: Interleukin-17A (IL-17A) is the signature cytokine produced by Th17 CD4+ T cells and has been tightly linked to autoimmune pathogenesis. In particular, the transcription factors NFAT and RORγt are known to activate Il17a transcription, although the detailed mechanism of action remains incompletely understood. Here, we show that the nuclear orphan receptor NR2F6 can attenuate the capacity of NFAT to bind to critical regions of the Il17a gene promoter. In addition, because NR2F6 binds to defined hormone response elements (HREs) within the Il17a locus, it interferes with the ability of RORγt to access the DNA. Consistently, NFAT and RORγt binding within the Il17a locus were enhanced in Nr2f6-deficient CD4+ Th17 cells but decreased in Nr2f6-overexpressing transgenic CD4+ Th17 cells. Taken together, our findings uncover an example of antagonistic regulation of Il17a transcription through the direct reciprocal actions of NR2F6 versus NFAT and RORγt. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
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23. Influence of an Ironman triathlon on sister chromatid exchanges and high frequency cells.
- Author
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Reichhold, Stefanie, Meisel, Marlies, Neubauer, Oliver, and Wagner, Karl-Heinz
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IRONMAN triathlons ,SISTER chromatid exchange ,CELLS ,EXERCISE physiology ,OXIDATIVE stress ,DNA damage - Abstract
Introduction Regular moderate exercise and its beneficial influence on health have already been well-investigated. However, information on high volume exercise which might lead to increased oxidative stress and DNA damage is still very limited. The purpose of the present study was to investigate the effect of an Ironman triathlon race (3.8 km swim, 180 km cycle, 42 km run) on genomic stability and a possible DNA damage. Materials and methods The sister chromatid exchange (SCE) assay is a cytogenic biomarker, which can be influenced by various factors such as oxidative stress that occurs during extreme endurance exercise. Within this study SCEs and high frequency cells (HFCs) were measured in peripheral blood lymphocytes of nine well trained male triathletes (age 38 ± 6 years; VO
2 peak 55.59 ± 2.97 ml/kg/min; height 179.1 ± 4.19 cm; weight 76.3 ± 4.27 kg). Blood samples were collected 48 h before and 24 h post race. Results The mean SCE frequency in the Ironman triathletes 2 days before the race was 6.55 ± 2.71 per metaphase, which was significantly higher than post race (5.69 ± 2.60 SCEs per metaphase, p < 0.05). Additionally the mean of HFCs significantly decreased from 11.06 ± 2.66 per metaphase before the race to 9.42 ± 3.74 per metaphase post race (p < 0.05). Conclusion The significant decrease of SCEs and HFCs after the Ironman triathlon race provides an indication of endogenous repair mechanisms or counterregulations, which seem to prevent DNA damages probably through releasing antioxidants. [ABSTRACT FROM AUTHOR]- Published
- 2007
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24. Coronin 1A is an essential regulator of the TGFβ receptor/SMAD3 signaling pathway in Th17 CD4+ T cells
- Author
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Kaminski, Sandra, Hermann-Kleiter, Natascha, Meisel, Marlies, Thuille, Nikolaus, Cronin, Shane, Hara, Hiromitsu, Fresser, Friedrich, Penninger, Josef M., and Baier, Gottfried
- Subjects
- *
TRANSFORMING growth factors , *CELL communication , *T cells , *IMMUNE response , *SPINAL cord , *IMMUNOMODULATORS , *AUTOIMMUNITY - Abstract
Abstract: Transforming growth factor β (TGFβ) plays a central role in maintaining immune homeostasis by regulating the initiation and termination of immune responses and thus preventing the development of autoimmune diseases. In this study, we describe an essential mechanism by which the actin regulatory protein Coronin 1A (Coro1A) ensures the proper response of Th17 CD4+ T cells to TGFβ. Coro1A has been established as a key player in T cell survival, migration, activation, and Ca2+ regulation in naive T cells. We show that mice lacking Coro1a developed less severe experimental autoimmune encephalomyelitis (EAE). Unexpectedly, upon the re-induction of EAE, Coro1a −/− mice exhibited enhanced EAE signs that correlated with increased numbers of IL-17 producing CD4+ cells in the central nervous system (CNS) compared to wild-type mice. In vitro differentiated Coro1a −/− Th17 CD4+ T cells consistently produced more IL-17 than wild-type cells and displayed a Th17/Th1-like phenotype in regard to the expression of the Th1 markers T-bet and IFNγ. Mechanistically, the Coro1a −/− Th17 cell phenotype correlated with a severe defect in TGFβR-mediated SMAD3 activation. Taken together, these data provide experimental evidence of a non-redundant role of Coro1A in the regulation of Th17 CD4+ cell effector functions and, subsequently, in the development of autoimmunity. [Copyright &y& Elsevier]
- Published
- 2011
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25. Fth1-mScarlet Reports Monocyte State during Lipopolysaccharide-induced Lung Inflammation.
- Author
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Michalides BA, Shoger KE, Kruszelnicki S, Cheemalavagu N, Martinez-Turak A, Jackson-Strong M, Laughlin CR, Betsur OS, Colby D, Meisel M, Gingras S, and Gottschalk RA
- Abstract
Monocytes and macrophages are central to host defense but also contribute to inflammation-associated pathology. Efforts to manipulate monocyte and macrophage function are limited by our ability to effectively quantify the functional programs of these cells. We identified the gene Fth1, which encodes the ferritin H chain, as highly predictive of alveolar macrophage transcriptomic states during LPS-induced lung inflammation and developed an Fth1-mScarlet reporter mouse. In the steady-state lung, high Fth1-mScarlet expression is restricted to alveolar macrophages. In response to LPS-induced lung inflammation, Fth1 reporter activity is robustly increased in monocytes, with its expression reporting genes that are differentially expressed in monocytes versus macrophages. Consistent with this reporter-associated gene profile, within the Lyz2-GFP+CD11b+Ly6C+ gate, the highest Fth1 reporter expression was observed in CD11c+ cells, indicative of monocyte-to-macrophage differentiation. Although Fth1-mScarlet was induced in monocytes responding to either TLR4 ligation or M-CSF-induced macrophage differentiation in vitro, TLR4-dependent expression occurred with greater speed and magnitude. Considering this, we suggest that Fth1-mScarlet expression reports monocyte-to-macrophage differentiation, with increased expression in proinflammatory states. Dissecting macrophage differentiation from inflammatory programs will be enhanced when combining Fth1-mScarlet with other reporter systems. Thus, the Fth1-mScarlet model addresses an important lack of tools to report the diverse spectrum of monocyte and macrophage states in vivo., (Copyright © 2024 by The American Association of Immunologists, Inc.)
- Published
- 2024
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- View/download PDF
26. Epigenetic control of commensal induced Th2 Responses and Intestinal immunopathology.
- Author
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Sangani KA, Parker ME, Anderson HD, Chen L, Pandey SP, Pierre JF, Meisel M, Riesenfeld SJ, Hinterleitner R, and Jabri B
- Abstract
Understanding the initiation of T-helper (Th)-2 immunity is crucial for addressing allergic diseases that have been linked to the commensal microbiota. However, Th2 responses are notably absent from known host-microbiota intestinal immune circuits. Notably, the commensal protist Tritrichomonas induces a transient innate ILC2 circuit rather than a chronic Th2 circuit. Canonical Th2 responses rely on the induction of IL-4 production by innate cells. This study shows that the absence of Tet2 , a DNA demethylase, reprograms naïve T cells to autonomously produce IL-4 upon T cell receptor stimulation, bypassing the need for IL-4 from innate cells for Th2 differentiation. Loss of this checkpoint induces chronic Th2 responses to Tritrichomonas , associated with IL-25-dependent barrier dysfunction and increased susceptibility to allergic pathology in response to dietary antigens., Sentence Summary: Regulation of cell autonomous IL-4 in T cells is critical to prevent dysregulated Th2 immunity to commensals and predisposition to allergy.
- Published
- 2024
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27. Dietary Commensal Wrestles Iron from Tumor Microenvironment to Activate Antitumoral Macrophages.
- Author
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Lee AH, Randhawa SK, and Meisel M
- Subjects
- Humans, Animals, Iron metabolism, CD8-Positive T-Lymphocytes immunology, Macrophages immunology, Macrophages metabolism, Macrophages drug effects, Macrophage Activation drug effects, Macrophage Activation immunology, Neoplasms immunology, Neoplasms microbiology, Neoplasms pathology, Lactobacillus plantarum, Mice, Tumor-Associated Macrophages immunology, Tumor-Associated Macrophages metabolism, Tumor-Associated Macrophages drug effects, Diet, Tumor Microenvironment immunology, Tumor Microenvironment drug effects
- Abstract
The microbiome dictates the response to cancer immunotherapy efficacy. However, the mechanisms of how the microbiota impacts therapy efficacy remain poorly understood. In a recent issue of Nature Immunology, Sharma and colleagues elucidate a multifaceted, macrophage-driven mechanism exerted by a specific strain of fermented food commensal plantarum strain IMB19, LpIMB19. LpIMB19 activates tumor macrophages, resulting in the enhancement of cytotoxic cluster differentiation 8 (CD8) T cells. LpIMB19 administration led to an expansion of tumor-infiltrating CD8 T cells and improved the efficacy of anti-PD-L1 therapy. Rhamnose-rich heteropolysaccharide, a strain-specific cell wall component, was identified as the primary effector molecule of LplMB19. Toll-like receptor 2 signaling and the ability of macrophages to sequester iron were both critical for rhamnose-rich heteropolysaccharide-mediated macrophage activation upstream of the CD8 T-cell effector response and contributed to tumor cell apoptosis through iron deprivation. These findings reveal a well-defined mechanism connecting diet and health outcomes, suggesting that diet-derived commensals may warrant further investigation. Additionally, this work emphasizes the importance of strain-specific differences in studying microbiome-cancer interactions and the concept of "nutritional immunity" to enhance microbe-triggered antitumor immunity., (©2024 American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
28. Altered hepatic and intestinal homeostasis in a neonatal murine model of short-term total parenteral nutrition and antibiotics.
- Author
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Mims TS, Kumari R, Leathem C, Antunes K, Joseph S, Yen MI, Ferstl D, Jamieson SM, Sabbar A, Biebel C, Lazarevic N, Willis NB, Henry L, Yen CE, Smith JP, Gosain A, Meisel M, Willis KA, Talati AJ, Elabiad MT, Hibl B, and Pierre JF
- Subjects
- Swine, Adult, Infant, Female, Pregnancy, Animals, Humans, Mice, Anti-Bacterial Agents pharmacology, Disease Models, Animal, Parenteral Nutrition, Total, Homeostasis, Animals, Genetically Modified, Cholestasis, Fatty Liver
- Abstract
Parenteral nutrition (PN) prevents starvation and supports metabolic requirements intravenously when patients are unable to be fed enterally. Clinically, infants are frequently provided PN in intensive care settings along with exposure to antibiotics (ABX) to minimize infection during care. Unfortunately, neonates experience extremely high rates of hepatic complications. Adult rodent and piglet models of PN are well-established but neonatal models capable of leveraging the considerable transgenic potential of the mouse remain underdeveloped. Utilizing our newly established neonatal murine PN mouse model, we administered ABX or controlled drinking water to timed pregnant dams to disrupt the maternal microbiome. We randomized mouse pups to PN or sham surgery controls +/- ABX exposure. ABX or short-term PN decreased liver and brain organ weights, intestinal length, and mucosal architecture (vs. controls). PN significantly elevated evidence of hepatic proinflammatory markers, neutrophils and macrophage counts, bacterial colony-forming units, and evidence of cholestasis risk, which was blocked by ABX. However, ABX uniquely elevated metabolic regulatory genes resulting in accumulation of hepatocyte lipids, triglycerides, and elevated tauro-chenoxycholic acid (TCDCA) in serum. Within the gut, PN elevated the relative abundance of Akkermansia, Enterococcus , and Suterella with decreased Anaerostipes and Lactobacillus compared with controls, whereas ABX enriched Proteobacteria. We conclude that short-term PN elevates hepatic inflammatory stress and risk of cholestasis in early life. Although concurrent ABX exposure protects against hepatic immune activation during PN, the dual exposure modulates metabolism and may contribute toward early steatosis phenotype, sometimes observed in infants unable to wean from PN. NEW & NOTEWORTHY This study successfully established a translationally relevant, murine neonatal parenteral nutrition (PN) model. Short-term PN is sufficient to induce hepatitis-associated cholestasis in a neonatal murine model that can be used to understand disease in early life. The administration of antibiotics during PN protects animals from bacterial translocation and proinflammatory responses but induces unique metabolic shifts that may predispose the liver toward early steatosis.
- Published
- 2023
- Full Text
- View/download PDF
29. Detection of viable commensal bacteria in murine melanoma tumors by culturomics.
- Author
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Phelps CM, Shapira JH, Laughlin CR, and Meisel M
- Subjects
- Animals, Mice, RNA, Ribosomal, 16S genetics, Bacteria genetics, Melanoma, Microbiota genetics
- Abstract
Emerging evidence suggests the tumor microbiome at gut-distal sites can modulate tumor immunity and response to cancer immunotherapy. However, detection of commensal bacteria at gut-distal tumor sites is challenging given their low abundance. Here, we present a culturomics approach to facilitate recovery of phylogenetically diverse live commensal bacteria within gut-distal melanoma tumors. We describe steps for media preparation, tissue isolation, tissue homogenization, and host cell lysis. We then detail broth expansion culture followed by agar culture and single-colony 16S rRNA sequencing. For complete details on the use and execution of this protocol, please refer to Bender and McPherson et al. (2023).
1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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- View/download PDF
30. Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment.
- Author
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Bender MJ, McPherson AC, Phelps CM, Pandey SP, Laughlin CR, Shapira JH, Medina Sanchez L, Rana M, Richie TG, Mims TS, Gocher-Demske AM, Cervantes-Barragan L, Mullett SJ, Gelhaus SL, Bruno TC, Cannon N, McCulloch JA, Vignali DAA, Hinterleitner R, Joglekar AV, Pierre JF, Lee STM, Davar D, Zarour HM, and Meisel M
- Subjects
- Humans, Diet, Immune Checkpoint Inhibitors, Tryptophan metabolism, CD8-Positive T-Lymphocytes immunology, Receptors, Aryl Hydrocarbon agonists, Limosilactobacillus reuteri metabolism, Melanoma therapy, Tumor Microenvironment
- Abstract
The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor (ICI) treatment. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances antitumor immunity and facilitates ICI in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (Lr) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 T cells, thereby bolstering ICI. Moreover, Lr-secreted I3A was both necessary and sufficient to drive antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated Lr's antitumor effects. Further, a tryptophan-enriched diet potentiated both Lr- and ICI-induced antitumor immunity, dependent on CD8 T cell AhR signaling. Finally, we provide evidence for a potential role of I3A in promoting ICI efficacy and survival in advanced melanoma patients., Competing Interests: Declaration of interests D.A.A.V.: cofounder and stock holder—Novasenta, Tizona, Trishula; stock holder—Oncorus, Werewolf; patents licensed and royalties—Novasenta, BMS; scientific advisory board member—Tizona, Werewolf, F-Star, Bicara, Apeximmune, T7/Imreg Bio; consultant—BMS, Almirall, Incyte, G1 Therapeutics, Inzen Therapeutics, Regeneron, Avidity Partners; research funding—BMS, Novasenta. A.V.J.: research funding—Mitsubishi Tanabe Pharma. J.F.P.: cofounder and stock holder—Gateway Biome Corporation. D.D.: grants/research support (institutional)—Arcus, CellSight Technologies, Immunocore, Merck, Regeneron Pharmaceuticals Inc., Tesaro/GSK; consultant: Clinical Care Options (CCO), Finch Therapeutics, Gerson Lehrman Group (GLG), Medical Learning Group (MLG), Xilio Therapeutics; CE Speakers’ Bureau—Castle Biosciences; intellectual Property includes US Patent 63/124,231, “compositions and methods for treating cancer,” December 11, 2020 and US Patent 63/208,719, “compositions and methods for determining responsiveness to immune checkpoint inhibitors (ICIs), increasing effectiveness of ICI and treating cancer,” June 9, 2021., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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31. Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis.
- Author
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Pandey SP, Bender MJ, McPherson AC, Phelps CM, Sanchez LM, Rana M, Hedden L, Sangani KA, Chen L, Shapira JH, Siller M, Goel C, Verdú EF, Jabri B, Chang A, Chandran UR, Mullett SJ, Wendell SG, Singhi AD, Tilstra JS, Pierre JF, Arteel GE, Hinterleitner R, and Meisel M
- Subjects
- Animals, Dysbiosis complications, Interferon-gamma, Ligands, Mice, T-Lymphocytes, Cytotoxic, DNA-Binding Proteins genetics, Dioxygenases genetics, Hepatitis, Autoimmune etiology, Hepatitis, Autoimmune pathology, Limosilactobacillus reuteri, Liver immunology, Liver microbiology, Microbiota genetics, Microbiota immunology
- Abstract
The triggers that drive interferon-γ (IFNγ)-producing CD8 T cell (Tc1 cell)-mediated autoimmune hepatitis (AIH) remain obscure. Here, we show that lack of hematopoietic Tet methylcytosine dioxygenase 2 (Tet2), an epigenetic regulator associated with autoimmunity, results in the development of microbiota-dependent AIH-like pathology, accompanied by hepatic enrichment of aryl hydrocarbon receptor (AhR) ligand-producing pathobionts and rampant Tc1 cell immunity. We report that AIH-like disease development is dependent on both IFNγ and AhR signaling, as blocking either reverts ongoing AIH-like pathology. Illustrating the critical role of AhR-ligand-producing pathobionts in this condition, hepatic translocation of the AhR ligand indole-3-aldehyde (I3A)-releasing Lactobacillus reuteri is sufficient to trigger AIH-like pathology. Finally, we demonstrate that I3A is required for L. reuteri-induced Tc1 cell differentiation in vitro and AIH-like pathology in vivo, both of which are restrained by Tet2 within CD8 T cells. This AIH-disease model may contribute to the development of therapeutics to alleviate AIH., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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32. High-sensitivity C-reactive protein is associated with clonal hematopoiesis of indeterminate potential.
- Author
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Busque L, Sun M, Buscarlet M, Ayachi S, Feroz Zada Y, Provost S, Bourgoin V, Mollica L, Meisel M, Hinterleitner R, Jabri B, Dubé MP, and Tardif JC
- Subjects
- Aged, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Hematopoietic Stem Cells, Humans, Male, C-Reactive Protein, Clonal Hematopoiesis, Hematopoiesis genetics, Percutaneous Coronary Intervention
- Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is predictive of hematological cancers and cardiovascular diseases, but the etiology of CHIP initiation and clonal expansion is unknown. Several lines of evidence suggest that proinflammatory cytokines may favor mutated hematopoietic stem cell expansion. To investigate the potential link between inflammation and CHIP, we performed targeted deep sequencing of 11 genes previously implicated in CHIP in 1887 subjects aged >70 years from the Montreal Heart Institute Biobank, of which 1359 had prior coronary artery disease (CAD), and 528 controls did not. We assessed association of CHIP with log transformed high-sensitivity C-reactive protein (hs-CRP), a validated biomarker of inflammation. CHIP was identified in 427 of the 1887 subjects (22.6%). CHIP mutations were more frequently identified in DNMT3A (11.6%) and TET2 (6.1%), with a higher proportion of TET2 mutations occurring in controls than in patients with CAD (9.0% vs 4.9%, P < .001). CHIP carriers had 21% higher hs-CRP levels compared with their noncarrier counterparts (eβ = 1.21, 95% confidence interval [CI]: 1.08 to 1.36; P = .001). A similar effect was observed in the subgroup of patients with known CAD (eβ = 1.22, 95% CI: 1.06 to 1.41; P = .005). These findings confirm the association between inflammation and CHIP. This association may open investigational avenues aimed at documenting mechanisms linking inflammation to clonal progression and ultimately supports prevention interventions to attenuate CHIP's impact on cardiovascular disease and cancer., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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33. Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APP SWE /PS1 ΔE9 murine model of Alzheimer's disease.
- Author
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Minter MR, Hinterleitner R, Meisel M, Zhang C, Leone V, Zhang X, Oyler-Castrillo P, Zhang X, Musch MW, Shen X, Jabri B, Chang EB, Tanzi RE, and Sisodia SS
- Subjects
- Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Protein Precursor metabolism, Amyloidosis metabolism, Amyloidosis pathology, Animals, Biodiversity, Biomarkers, Brain metabolism, Brain pathology, Disease Models, Animal, Gastrointestinal Microbiome, Inflammation Mediators metabolism, Male, Metagenome, Metagenomics methods, Mice, Mice, Transgenic, Neuroimmunomodulation drug effects, Neuroimmunomodulation genetics, Neuroimmunomodulation immunology, Plaque, Amyloid etiology, Plaque, Amyloid metabolism, Plaque, Amyloid pathology, RNA, Ribosomal, 16S genetics, Alzheimer Disease etiology, Amyloid beta-Protein Precursor genetics, Amyloidosis genetics, Anti-Bacterial Agents pharmacology, Microbiota drug effects
- Abstract
Recent evidence suggests the commensal microbiome regulates host immunity and influences brain function; findings that have ramifications for neurodegenerative diseases. In the context of Alzheimer's disease (AD), we previously reported that perturbations in microbial diversity induced by life-long combinatorial antibiotic (ABX) selection pressure in the APP
SWE /PS1ΔE9 mouse model of amyloidosis is commensurate with reductions in amyloid-β (Aβ) plaque pathology and plaque-localised gliosis. Considering microbiota-host interactions, specifically during early post-natal development, are critical for immune- and neuro-development we now examine the impact of microbial community perturbations induced by acute ABX exposure exclusively during this period in APPSWE /PS1ΔE9 mice. We show that early post-natal (P) ABX treatment (P14-P21) results in long-term alterations of gut microbial genera (predominantly Lachnospiraceae and S24-7) and reduction in brain Aβ deposition in aged APPSWE /PS1ΔE9 mice. These mice exhibit elevated levels of blood- and brain-resident Foxp3+ T-regulatory cells and display an alteration in the inflammatory milieu of the serum and cerebrospinal fluid. Finally, we confirm that plaque-localised microglia and astrocytes are reduced in ABX-exposed mice. These findings suggest that ABX-induced microbial diversity perturbations during post-natal stages of development coincide with altered host immunity mechanisms and amyloidosis in a murine model of AD.- Published
- 2017
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34. Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis.
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Meisel M, Mayassi T, Fehlner-Peach H, Koval JC, O'Brien SL, Hinterleitner R, Lesko K, Kim S, Bouziat R, Chen L, Weber CR, Mazmanian SK, Jabri B, and Antonopoulos DA
- Subjects
- Animals, Bacteria classification, Bacteria genetics, Bacteria isolation & purification, Colitis genetics, Colitis microbiology, Colitis therapy, Disease Susceptibility, Dysbiosis genetics, Dysbiosis metabolism, Fecal Microbiota Transplantation, Feces microbiology, Female, Germ-Free Life, Humans, Interleukin-15 genetics, Intestinal Mucosa metabolism, Intestinal Mucosa microbiology, Male, Mice, Mice, Inbred C57BL, Bacteria metabolism, Butyrates metabolism, Colitis metabolism, Dysbiosis microbiology, Gastrointestinal Microbiome, Interleukin-15 metabolism, Intestines microbiology
- Abstract
Dysbiosis resulting in gut-microbiome alterations with reduced butyrate production are thought to disrupt intestinal immune homeostasis and promote complex immune disorders. However, whether and how dysbiosis develops before the onset of overt pathology remains poorly defined. Interleukin-15 (IL-15) is upregulated in distressed tissue and its overexpression is thought to predispose susceptible individuals to and have a role in the pathogenesis of celiac disease and inflammatory bowel disease (IBD). Although the immunological roles of IL-15 have been largely studied, its potential impact on the microbiota remains unexplored. Analysis of 16S ribosomal RNA-based inventories of bacterial communities in mice overexpressing IL-15 in the intestinal epithelium (villin-IL-15 transgenic (v-IL-15tg) mice) shows distinct changes in the composition of the intestinal bacteria. Although some alterations are specific to individual intestinal compartments, others are found across the ileum, cecum and feces. In particular, IL-15 overexpression restructures the composition of the microbiota with a decrease in butyrate-producing bacteria that is associated with a reduction in luminal butyrate levels across all intestinal compartments. Fecal microbiota transplant experiments of wild-type and v-IL-15tg microbiota into germ-free mice further indicate that diminishing butyrate concentration observed in the intestinal lumen of v-IL-15tg mice is the result of intrinsic alterations in the microbiota induced by IL-15. This reconfiguration of the microbiota is associated with increased susceptibility to dextran sodium sulfate-induced colitis. Altogether, this study reveals that IL-15 impacts butyrate-producing bacteria and lowers butyrate levels in the absence of overt pathology, which represent events that precede and promote intestinal inflammatory diseases.
- Published
- 2017
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35. Protein kinase C θ regulates the phenotype of murine CD4+ Th17 cells.
- Author
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Wachowicz K, Hermann-Kleiter N, Meisel M, Siegmund K, Thuille N, and Baier G
- Subjects
- Animals, Blotting, Western, CD4-Positive T-Lymphocytes metabolism, Cell Differentiation genetics, Cells, Cultured, Encephalomyelitis, Autoimmune, Experimental genetics, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental metabolism, Female, Flow Cytometry, Interferon-gamma genetics, Interferon-gamma immunology, Interferon-gamma metabolism, Interferon-gamma pharmacology, Interleukin-17 immunology, Interleukin-17 metabolism, Interleukin-23 immunology, Interleukin-23 pharmacology, Isoenzymes deficiency, Isoenzymes genetics, Mice, Knockout, Myelin-Oligodendrocyte Glycoprotein immunology, Peptide Fragments immunology, Phenotype, Phosphorylation immunology, Protein Kinase C deficiency, Protein Kinase C genetics, Protein Kinase C-theta, Reverse Transcriptase Polymerase Chain Reaction, STAT1 Transcription Factor immunology, STAT1 Transcription Factor metabolism, STAT4 Transcription Factor immunology, STAT4 Transcription Factor metabolism, T-Box Domain Proteins genetics, T-Box Domain Proteins immunology, Th1 Cells immunology, Th1 Cells metabolism, Th17 Cells metabolism, CD4-Positive T-Lymphocytes immunology, Cell Differentiation immunology, Isoenzymes immunology, Protein Kinase C immunology, Th17 Cells immunology
- Abstract
Protein kinase C θ (PKCθ) is involved in signaling downstream of the T cell antigen receptor (TCR) and is important for shaping effector T cell functions and inflammatory disease development. Acquisition of Th1-like effector features by Th17 cells has been linked to increased pathogenic potential. However, the molecular mechanisms underlying Th17/Th1 phenotypic instability remain largely unknown. In the current study, we address the role of PKCθ in differentiation and function of Th17 cells by using genetic knock-out mice. Implementing in vitro (polarizing T cell cultures) and in vivo (experimental autoimmune encephalomyelitis model, EAE) techniques, we demonstrated that PKCθ-deficient CD4+ T cells show normal Th17 marker gene expression (interleukin 17A/F, RORγt), accompanied by enhanced production of the Th1-typical markers such as interferon gamma (IFN-γ) and transcription factor T-bet. Mechanistically, this phenotype was linked to aberrantly elevated Stat4 mRNA levels in PKCθ-/- CD4+ T cells during the priming phase of Th17 differentiation. In contrast, transcription of the Stat4 gene was suppressed in Th17-primed wild-type cells. This change in cellular effector phenotype was reflected in vivo by prolonged neurological impairment of PKCθ-deficient mice during the course of EAE. Taken together, our data provide genetic evidence that PKCθ is critical for stabilizing Th17 cell phenotype by selective suppression of the STAT4/IFN-γ/T-bet axis at the onset of differentiation.
- Published
- 2014
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36. Coronin 1A is an essential regulator of the TGFβ receptor/SMAD3 signaling pathway in Th17 CD4(+) T cells.
- Author
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Kaminski S, Hermann-Kleiter N, Meisel M, Thuille N, Cronin S, Hara H, Fresser F, Penninger JM, and Baier G
- Subjects
- Animals, Cell Differentiation immunology, Cell Movement immunology, Disease Models, Animal, Female, Flow Cytometry, Interferon-gamma biosynthesis, Interleukin-17 biosynthesis, Lupus Erythematosus, Systemic metabolism, Lupus Erythematosus, Systemic pathology, Mice, Mice, Knockout, Microfilament Proteins deficiency, Microfilament Proteins genetics, Real-Time Polymerase Chain Reaction, Receptors, Transforming Growth Factor beta genetics, Receptors, Transforming Growth Factor beta immunology, Signal Transduction genetics, Smad3 Protein genetics, Smad3 Protein immunology, Th1 Cells immunology, Th1 Cells metabolism, Th17 Cells immunology, Th17 Cells metabolism, Transforming Growth Factor beta immunology, Gene Expression immunology, Lupus Erythematosus, Systemic immunology, Microfilament Proteins immunology, Receptors, Transforming Growth Factor beta metabolism, Signal Transduction immunology, Smad3 Protein metabolism, Transforming Growth Factor beta metabolism
- Abstract
Transforming growth factor β (TGFβ) plays a central role in maintaining immune homeostasis by regulating the initiation and termination of immune responses and thus preventing the development of autoimmune diseases. In this study, we describe an essential mechanism by which the actin regulatory protein Coronin 1A (Coro1A) ensures the proper response of Th17 CD4(+) T cells to TGFβ. Coro1A has been established as a key player in T cell survival, migration, activation, and Ca(2+) regulation in naive T cells. We show that mice lacking Coro1a developed less severe experimental autoimmune encephalomyelitis (EAE). Unexpectedly, upon the re-induction of EAE, Coro1a(-/-) mice exhibited enhanced EAE signs that correlated with increased numbers of IL-17 producing CD4(+) cells in the central nervous system (CNS) compared to wild-type mice. In vitro differentiated Coro1a(-/-) Th17 CD4(+) T cells consistently produced more IL-17 than wild-type cells and displayed a Th17/Th1-like phenotype in regard to the expression of the Th1 markers T-bet and IFNγ. Mechanistically, the Coro1a(-/-) Th17 cell phenotype correlated with a severe defect in TGFβR-mediated SMAD3 activation. Taken together, these data provide experimental evidence of a non-redundant role of Coro1A in the regulation of Th17 CD4(+) cell effector functions and, subsequently, in the development of autoimmunity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
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