Dysbiotic microbiome triggers Th17 cells to mediate oral mucosal immunopathology in mice and humans
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE118166 | GEO | 2018/12/31
REPOSITORIES: GEO
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Project description:Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, we demonstrate an expansion of resident memory T helper 17 (TH17) cells in human periodontitis. Phenocopying humans, TH17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral TH17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)-dependent manner, periodontitis-associated expansion of TH17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. TH17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of TH17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in TH17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Our study highlights distinct functions of TH17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.
| S-EPMC6330016 | biostudies-literature
Project description:Dysbiotic microbiome triggers Th17 cells to mediate oral mucosal immunopathology in mice and humans
| PRJNA484734 | ENA
Project description:At mucosal surfaces, epithelial cells provide a structural barrier and an immune defense system. However, dysregulated epithelial responses can contribute to disease states. Here, we demonstrate that epithelial intrinsic production of IL-23 triggers an inflammatory loop in the prevalent oral disease, periodontitis. Epithelial IL-23 expression localized to areas proximal to the disease-associated microbiome, is evident both in experimental models and in patients with common and genetic forms of disease. Mechanistically, flagellated microbial species of the periodontitis microbiome, trigger epithelial IL-23 induction in a TLR5-dependent manner. Intriguingly, unlike other Th17-driven diseases, here non-hematopoietic cell-derived IL-23 serves as an initiator of pathogenic inflammation. Beyond periodontitis, analysis of publicly available datasets reveals expression of epithelial IL-23 in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human disease. Collectively, this work highlights an unappreciated role for the barrier epithelium in the induction of IL-23-mediated inflammation.
2024-05-08 | GSE243173 | GEO
Project description:The interleukin-17 (IL-17) family of cytokines phylogenetically predates the evolution of T cells in jawed vertebrates, suggesting that the ontogeny of the Th17 cell lineage must have arisen to confer an evolutionary advantage to the host over innate sources of IL-17. Utilizing a model of mucosal immunization with the encapsulated bacteria Klebsiella pneumoniae, we found that B cells, which largely recognized polysaccharide capsular antigens, afforded protection to only the vaccine strain. In contrast, memory Th17 cells proliferated in response to conserved outer membrane proteins and conferred protection against several serotypes of K. pneumoniae, including the recently described multidrug resistant New Dehli metallolactamase strain. Notably, this heterologous, clade-specific protection was antibody independent, demonstrating the Th17 cell lineage confers a host advantage by providing heterologous mucosal immunity independent of serotype-specific antibody.
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Project description:BackgroundThe release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the molecular mechanisms underlying the release of NETs in COVID-19 remain unclear.ObjectivesWe aim to investigate the role of the Gasdermin-D (GSDMD) pathway on NETs release and the development of organ damage during COVID-19.MethodsWe performed a single-cell transcriptome analysis in public data of bronchoalveolar lavage. Then, we enrolled 63 hospitalized patients with moderate and severe COVID-19. We analyze in blood and lung tissue samples the expression of GSDMD, presence of NETs, and signaling pathways upstreaming. Furthermore, we analyzed the treatment with disulfiram in a mouse model of SARS-CoV-2 infection.ResultsWe found that the SARS-CoV-2 virus directly activates the pore-forming protein GSDMD that triggers NET production and organ damage in COVID-19. Single-cell transcriptome analysis revealed that the expression of GSDMD and inflammasome-related genes were increased in COVID-19 patients. High expression of active GSDMD associated with NETs structures was found in the lung tissue of COVID-19 patients. Furthermore, we showed that activation of GSDMD in neutrophils requires active caspase1/4 and live SARS-CoV-2, which infects neutrophils. In a mouse model of SARS-CoV-2 infection, the treatment with disulfiram inhibited NETs release and reduced organ damage.ConclusionThese results demonstrated that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology and suggests GSDMD as a novel potential target for improving the COVID-19 therapeutic strategy.
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Project description:Clinically, obesity is strongly associated with severe TH2 immunopathology, though the physiological, cellular, and molecular underpinnings of this association remain obscure. We demonstrate that obese mice are susceptible to severe atopic dermatitis (AD), a major manifestation of TH2 immunopathology and disease burden in humans. Mechanistically, we show that dysregulation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARg) in T cells is a causal link between obesity and the increased TH2 immunopathology. We find that PPARg directly controls a cellular metabolic transcriptional program that restrains nuclear gene expression of the chief TH2 effector cytokines interleukin-4 (IL-4) and interleukin-13 (IL-13). Accordingly, thiazolidinediones (TZDs), potent PPARg agonists, robustly protect obese mice from TH2 immunopathology. Collectively, these findings establish PPARg as a molecular link between obesity and TH2 immune homeostasis and identify TZDs as novel therapeutic candidates for TH2 immunopathology.
2022-03-29 | GSE189216 | GEO
Project description:ADAR1 mutation causes ZBP1-dependent immunopathology
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Project description:Plasminogen (Plg), the zymogen precursor of the serine protease plasmin, is synthesized by the liver and is present in high concentration in the circulation and in interstitial fluids to provide focal proteolysis, after being converted to plasmin by urokinase or tissue plasminogen activator. Homozygous or compound heterozygous mutations in the human Plg gene (PLG) typically lead to severe mucosal disease involvement suggesting, a critical role for this gene/pathway in mucosal immunity. Indeed, such patients present with deposition of fibrin at various mucosal sites leading to ocular disease (conjunctivitis), oral mucosal disease (ligneous periodontitis), lung, vaginal and gastrointestinal tract involvement. In the oral mucosa, local deposition of fibrin is hypothesized to lead to severe soft tissue and bone destruction around teeth and often loss of the entire dentition in adolescence. Mucosal inflammation in areas surrounding the dentition and destruction of underlying bone are also the hallmarks of the common human oral mucosal disease, periodontitis. Plg-deficient mice phenocopy the human disease and we aim to use this animal model to understand the mechanism underlying fibrin-mediated periodontal immunopathology in vivo. Herein, we analyse the transcriptome of gingival tissues extracted from Plg-deficient mice in comparison to their wild-type littermates at 12 weeks of age.
2022-06-02 | GSE178616 | GEO
Project description:CD4 T cells promote innate and adaptive immune responses, but how vaccine-elicited CD4 T cells contribute to immune protection remains unclear. Here we evaluated whether induction of virus-specific CD4 T cells by vaccination would protect mice against infection with chronic lymphocytic choriomeningitis virus (LCMV). Immunization with vaccines that selectively induced CD4 T cell responses resulted in catastrophic inflammation and mortality following challenge with a persistent form of LCMV. Immunopathology required antigen-specific CD4 T cells and was associated with a cytokine storm, generalized inflammation, and multi-organ system failure. Virus-specific CD8 T cells or antibodies abrogated the pathology. These data demonstrate that vaccine-elicited CD4 T cells in the absence of effective antiviral immune responses can trigger lethal immunopathology. Splenic GP66-specific CD4 T cells from mice immunized with either a LMwt vaccine (sham) or LMgp61 vaccine (CD4 vaccine) were purified by FACS on day 8 post-infection with LCMV clone 13
2014-12-04 | E-GEOD-63825 | biostudies-arrayexpress