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Sodium chloride generates anti-inflammatory Th17 cell responses but amplifies Th17 cell pathogenicity in pro-inflammatory cytokine microenvironments

ABSTRACT: T helper cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here we demonstrate that high NaCl conditions induced a stable, pathogen-specific, anti-inflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and interleukin (IL)-17-expression in high-NaCl conditions. The NaCl-induced acquisition of an anti-inflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a pro-inflammatory and TGF--low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148669 | GEO | 2020/04/15

REPOSITORIES: GEO

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Sodium chloride generates anti-inflammatory Th17 cell responses but amplifies Th17 cell pathogenicity in pro-inflammatory cytokine microenvironments

Project description:Sodium chloride generates anti-inflammatory Th17 cell responses but amplifies Th17 cell pathogenicity in pro-inflammatory cytokine microenvironments

| PRJNA625315 | ENA

A pathogenic Th17/CD38+ macrophage feedback loop drives inflammatory arthritis through TNFa

Project description:The pathobiology of rheumatoid inflammatory diseases, including rheumatoid arthritis (RA) and psoriatic arthritis (PsA), involves the interplay between innate and adaptive immune components and resident synoviocytes. Single-cell analyses of patient samples and relevant mouse models have characterized many cellular subsets in RA. However, the impact of interactions between cell types is not fully understood. Here, we temporally profiled murine arthritic synovial isolates at the single-cell level to identify perturbations like those found in human RA. Notably, murine macrophage subtypes like those in RA patients were expanded in arthritis and linked to promoting the function of Th17 cells in the joint. In vitro experiments identified a capacity for murine macrophages to maintain the functionality and expansion of Th17 cells. Reciprocally, murine Th17 cell-derived TNFa induced CD38+ macrophages that enhanced Th17 functionality. Murine synovial CD38+ macrophages were expanded during arthritis and their depletion or blockade via TNFa-neutralization alleviated disease while reducing IL-17A-producing cells. These findings identify a cellular feedback loop that promotes Th17 cell pathogenicity through TNFa to drive inflammatory arthritis.

2022-01-05 | GSE184609 | GEO

ChIP-seq of H3K18la in murine Th17-differentiated T cells

Project description:Increased lactate levels in the tissue microenvironment are a well-known feature of chronic inflammation. However, the role of lactate in regulating T cell function remains controversial. We here demonstrate that extracellular lactate predominantly induces deregulation of the Th17-specific gene expression program by modulating metabolic and epigenetic status of Th17 cells. Following lactate treatment, Th17 cells significantly reduced their IL-17A production and upregulated Foxp3 expression through ROS-driven IL-2 secretion. Moreover, we observed a broad pattern of histone lactylation at various genes in CD4+ T cells, with particularly highly enriched lactylation of histone H3 at the Foxp3 promoter regions in lactate-treated Th17 cells. These results indicate that lactate is capable of reprogramming pro-inflammatory T cell phenotype into regulatory T cells. Moreover, we show that high lactate concentrations suppress the Th17 pathogenicity during intestinal inflammation. Collectively, these findings have a potential therapeutic value for development of novel clinical strategies to target inflammatory and autoimmune diseases.

2022-11-25 | GSE208727 | GEO

Transcriptional signature of human pro-inflammatory TH17 cells [TH17 clones]

Project description:Transcriptional signature of human pro-inflammatory TH17 cells [TH17 clones]

| PRJNA408016 | ENA

Genetic and pharmacological inhibition of the nuclear receptor RORa regulates Th17 driven inflammatory disorders

Project description:Full development of IL-17 producing CD4+ T helper cells (TH17 cells) requires the transcriptional activity of both orphan nuclear receptors RORa and RORgt. Despite this evidence, RORa is considered functionally redundant to RORgt; thus, the function and therapeutic value of RORa in TH17 cells remains underexplored. Using mouse models of autoimmune and chronic inflammation, we show that expression of RORa is required for TH17 cell pathogenicity. T-cell specific deletion of RORa reduced the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation was associated with decreased TH17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3+ T regulatory (Treg) cells. Importantly, inhibition of RORa with a selective small molecule antagonist largely phenocopied our genetic data, potently suppressing the in vivo development of both chronic/progressive and relapsing/remitting EAE but had no effect on overall thymic cellularity. Furthermore, use of the RORa antagonist effectively inhibited human TH17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORa acts independently of RORgt in programming TH17 pathogenicity and identifies RORa as a safer and more selective therapeutic target for the treatment of TH17-mediated autoimmunity.

2020-10-29 | GSE160327 | GEO

Transcriptional signature of human pro-inflammatory TH17 cells [TH17 clones]

Project description:Human IL-10– and IL-10+ TH17 clones maintained their pro- or anti-inflammatory characteristics after long-term culture. There were similarities between human IL-10– vs. IL-10+ TH17 clones and mouse pathogenic vs. non-pathogenic TH17 cells.

2017-09-29 | GSE104023 | GEO

The intestine harbours functionally distinct tissue-resident and inflammatory Th17 cells

Project description:Th17 cells are extensively studied because of their known pathogenic role in many inflammatory diseases, but are also important to support the integrity of the intestinal barrier in a non-inflammatory manner. Since therapeutic targeting of Th17 cell mediated pathologies carries the risk of inadvertently affecting protective Th17 cells, we set out to define the major distinctions between homeostatic tissue-resident Th17 cells and Th17 cells engaged in inflammatory reactions, focusing on the gut. We show here that homeostatic Th17 cells exhibit little plasticity towards expression of inflammatory cytokines, are characterised by a metabolism typical for quiescent or memory T cells, and do not participate in inflammatory processes. Infection-induced Th17 cells, on the other hand, show extensive plasticity towards pro-inflammatory cytokines, disseminate widely into the periphery and engage aerobic glycolysis in addition to oxidative phosphorylation typical for inflammatory effector cells.

2019-06-28 | GSE130302 | GEO

CIP2A negatively regulates Th17 differentiation

Project description:Interleukin 17 (IL-17) producing T helper 17 (Th17) cells are critical drivers of pathogenesis in a variety of autoimmune and inflammatory diseases. Strategies to mitigate excessive Th17 response thus remain an attractive target for immunotherapies. Here we report that Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) regulates IL-17 production by Th17 cells in human and mouse. Using CIP2A knock-out (KO) mice and siRNA-mediated CIP2A silencing in human primary CD4+ T cells, we demonstrated that CIP2A silencing results in a significant increase in IL-17 production. Interestingly, CIP2A deficient Th17 cells were characterized by increased strength and duration of STAT3 (Y705) phosphorylation. Genome-wide gene expression profile as well as the p-STAT3 (Y705) interactome of CIP2A deficient Th17 cells identified that CIP2A regulates the strength of the interaction between Acylglycerol kinase (AGK) and STAT3, and thereby, modulates STAT3 phosphorylation as well as expression of IL-17 in Th17 cells. Our results uncover the physiological function of CIP2A in Th17 cells and provides new opportunities for therapeutic intervention in Th17 cell mediated diseases.

2020-05-26 | PXD010612 | Pride

The cytokine IL-17A limits Th17 pathogenicity via a negative feedback loop driven by autocrine induction of IL-24

Project description:Dysregulated Th17 cell responses underlie multiple inflammatory and autoimmune diseases, including autoimmune uveitis and its animal model, EAU. However, clinical trials targeting IL-17A in uveitis were not successful. Here, we found that Th17 cells were regulated by their own signature cytokine, IL-17A. Loss of IL-17A in autopathogenic Th17 cells did not reduce their pathogenicity and instead elevated their expression of the Th17 cell cytokines GM-CSF and IL-17F. Mechanistic in vitro studies revealed a Th17 cell-intrinsic autocrine loop triggered by binding of IL-17A to its receptor, leading to activation of transcription factor NFκB and induction of IL 24, which repressed the Th17 cytokine program. In vivo, IL-24 treatment ameliorated Th17-induced EAU, whereas silencing of IL-24 in Th17 cells enhanced disease. This regulatory pathway also operated in human Th17 cells. Thus, IL-17A limits pathogenicity of Th17 cells by inducing IL-24. These findings may explain the disappointing therapeutic effect in targeting IL-17A in uveitis.

2020-07-22 | GSE152534 | GEO

Autoimmunity and infection give rise to distict inflammatory Th17 subsets [single-cell RNA-seq]

Project description:Th17 cells are a heterogeneous population that is critical for tissue homeostasis and inflammation during clearance of infections and autoimmunity. Despite substantial efforts distinguishing homeostatic and inflammatory roles of Th17 cells, the mechanism underlying the divergent functions of inflammatory Th17 cells is poorly understood. In this study, we show that the inflammatory Th17 engaged in autoimmune colitis and those involved in infection-induced colitis are two distinguishable populations illustrated by their distinct responses to a pharmacological molecule, clofazimine (CLF). Distinct from existing Th17 inhibitors, CLF selectively inhibits pro-autoimmune Th17 cells while preserving the functional state of infection-elicited Th17 cells through restricting Aldh1l2expression. Using single-cell RNA sequencing, we explored inflammatory Th17 transcriptional response to CLF from the colonic tissue of mice during autoimmune colitis and Citrobacter rodentiuminfection using Rorc gfp/+ reportor mice. Notably, we identified a unique suppression in the transcription of signature inflammatory genes in Th17 cells from autoimmune colitis with a marginal effect on those elicited by infection. Additionally, we illustrate with these data that the transcriptionally programming of pro-autoimmune Th17 cells are, indeed, unique compared to infection-elicited Th17 cells. Finally, we analyzed the impact of CLF on human inflammatory Th17 cells from the inflammed colon of a patient with IBD.

2023-06-13 | GSE234592 | GEO

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