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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE152534 | GEO | 2020/07/22

REPOSITORIES: GEO

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Ikzf1 lactylation regulates CD4 T cell differentiation

Project description:Dysregulation of Th17 differentiation was implicated in multiple inflammatory and autoimmune diseases including autoimmune uveitis. In the current study, we have provided evidence indicating that lactate-derived lactylation plays important roles in regulating Th17 differentiation. The lactylation level of CD4+ T cells was upregulated in EAU mice and inhibiting lactylation resulted in impaired EAU progression. We characterized the global lactylome of CD4+ T cells of normal and EAU mice. We found that the differentially lactylated proteins were enriched in pathways related to immune responses including leukocyte differentiation. Importantly, our results show that the lactylation level of Ikzf1 (K164) functions in regulating Th17 differentiation by differentially modulating gene expression patterns which are related to CD4+ T cell differentiation by CUT& Tag analysis. In view of the above mentioned well-documented evidence, Ikzf1 lactylation might represent an important regulator for Th17 differentiation in autoimmune uveitis.

2023-08-28 | GSE226678 | GEO

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

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

| PRJNA639596 | ENA

Gene Expression Profiling of IL-17A-treated Synovial Fibroblasts from the Human Temporomandibular Joint

Project description:Synovial fibroblasts contribute to the inflammatory temporomandibular joint under pathogenic stimuli. Synovial fibroblasts and T cells participate in the perpetuation of joint inflammation in a mutual activation feedback, via secretion of cytokines and chemokines that stimulate each other. IL-17 is an inflammatory cytokine produced primarily by Th17 cells that plays critical roles in the pathogenesis of numerous autoimmune and inflammatory diseases. Here, we investigated the roles of IL-17A in temporomandibular joint disorders (TMD) by using genome-wide analysis of synovial fibroblasts isolated from patients with TMD. We analyzed the gene expression profiles of synovial fibroblasts that were treated with or without IL-17A. IL-17 induced gene expression in synovial fibroblasts from human temporomandibular joint was measured at 4 hours after treated with IL-17A (10 ng/ml) and untreated control samples. This experiment used one donor sample.

2015-11-05 | E-GEOD-74668 | biostudies-arrayexpress

Foxo1 Drives the TGFβ1-Dependent Dichotomy of Th17 Cell Fates

Project description:T-helper 17 (Th17) cells play a dual role in immunological responses, serving as essential components in tissue homeostasis and host defense against microbial pathogens, while also contributing to proinflammatory conditions and autoimmunity. While Transforming Growth Factor-beta 1 (TGFβ1) is pivotal for the differentiation of non-pathogenic Th17 cells, the role of TGFβ3 and Activin in steering Th17 cells toward a pathogenic phenotype has been acknowledged. However, the molecular mechanisms governing this dichotomy remain elusive. In this study, we demonstrate that the transcription factor Foxo1 is upregulated in a TGFβ1 dose-dependent manner, serving as a critical regulator that specifically modulates the fate of pathogenic Th17 cells. Analyses in both uveitis patients and an Experimental Autoimmune Uveitis (EAU) mouse model reveal a strong correlation between disease severity and diminished Foxo1 expression levels. Ectopic expression of Foxo1 selectively attenuates IL-17A production under pathogenic Th17-inducing conditions. Moreover, enhanced Foxo1 expression, triggered by TGFβ1 signaling, is implicated in fatty acid metabolism pathways that favor non-pathogenic Th17 differentiation. Our drug screening identifies several FDA-approved compounds capable of upregulating Foxo1. Collectively, our findings offer compelling evidence that Foxo1 serves as a molecular switch to specifically control pathogenic versus non-pathogenic Th17 differentiation in a TGFβ1-dependent manner. These insights suggest that targeting Foxo1 could be a promising therapeutic strategy for autoimmune diseases, offering efficacy without compromising immune homeostasis.

2023-10-10 | GSE244599 | GEO

Glycosylation-dependent modulation of the IL-2 signaling axis determines Th17 differentiation and IL-10 production

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2020-03-29 | GSE129028 | GEO

Gene Expression Profiling of IL-17A-treated Synovial Fibroblasts from the Human Temporomandibular Joint

2015-11-05 | GSE74668 | GEO

CMTM4 is a subunit of the IL-17 receptor and mediates autoimmune pathology

Project description:Interleukin-17A (IL-17A) is a key mediator of protective immunity to yeast and bacterial infections but also drives the pathogenesis of several autoimmune diseases, such as psoriasis or psoriatic arthritis. Here, we show that the tetra-transmembrane protein CMTM4 is a subunit of the IL-17 receptor (IL-17R). CMTM4 constitutively associated with IL-17R subunit C (IL-17RC) to mediate its stability, posttranslational modification, and plasma membrane localization. Both mouse and human cell lines deficient in CMTM4 were largely unresponsive to IL-17A, due to their inability to assemble the IL-17 receptor signaling complex. Accordingly, CMTM4-deficient mice were largely resistant to experimental psoriasis. Collectively, our data identified CMTM4 as an essential component of the IL-17 receptor and a potential therapeutic target for treating IL-17-mediated autoimmune diseases.

2022-12-02 | PXD036366 | Pride

Genome expression profile for CD3+ T cells treated by nimodipine in EAU model

Project description:Uveitis is a severe autoimmune disease characereized by retinal inflammation, whicn brings harms to the visual function of the patients. We found that nimodipine could protect annimals from experimental autoimmune uveitis. To further clarify the possible mechanism through which nimodipine exerted effect, we performed genomic expression profiling of CD3+ T cells in EAU model and nimodipine treated group.

2021-09-03 | GSE183165 | GEO

Single-cell RNA sequencing reveals CD74high CCL5high retinal microglia initiating immune cells infiltration in autoimmune uveoretinitis

Project description:In this study, we found that microglia have a considerable number of cells compared to T cells, indicating an equally critical role of microglia in the progression of autoimmune uveitis. We further identified a specific microglial subpopulation expressed with high levels of CD74 and CCL5, which may be directly related to inflammation regulation in autoimmune uveitis and named inflammation-associated microglia (IAMs). Decreasing the number of IAMs by gene regulation methods or CD74/CCL5 neutralizing antibodies effectively reduced inflammation in EAU mice and delayed disease progression. A mechanistic study indicated that the CD74/CCL5 axis was mainly responsible for the regulation of the immune response in autoimmune uveitis. The intracytoplasmic domain of CD74 (CD74–ICD) may be cleaved by the SPPL2A protease and then activate the NF-kB-dependent inflammation pathway in IAM, resulting in the production of CCL5, which recruits peripheral T cells into the retina and causes an inflammatory burst in autoimmune uveitis mice. Decreasing the level of CD74 or CCL5 could effectively reduce uveitogenic T cell infiltration and relieve the autoimmune response in EAU mouse models, indicating the potential therapeutic value of CD74 and CCL5 in autoimmune uveitis.

2022-11-11 | GSE191260 | GEO

Gene expression profile of human epidermal keratinocytes in response to IFNgamma, IL-4, IL-6, IL-17A and IL-22

Project description:To understand the role of epidermal keratinocytes in immunopathology of skin diseases with predominant T helper (Th) cell responses, we measured the genome-wide transcriptional profile of human keratinocytes in response to IFNgamma, IL-4, IL-17A or IL-22, major cytokines produced by Th1, Th2, Th17 or Th22 cells, respectively. IL-6 was also included in the transcriptional profile analysis because a variety of pro-inflammatory stimuli stimulate human keratinocytes to produce IL-6 that has an autocrine or paracrine role in epidermal immunity. We aimed to discover commonly expressed genes in human keratinocytes in response to pro-inflammatory cytokines, which would be associated with common pathophysiological responses in various skin diseases such as skin permeability barrier disruption or epidermal hyperplasia. Normal human keratinocytes (NHKs) were stimulated with IFNγ, IL-4, IL-6, IL-17A and IL-22 for 24 hours and harvested for total RNA extraction and hybridization on Affymetrix microarrays.

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