IL-36 signaling in keratinocytes controls early IL-23 production in Aldara®-induced skin inflammation in mice
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PROVIDER: PRJNA601253 | ENA |
REPOSITORIES: ENA
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Project description:IL-36R signaling plays an important role in the pathogenesis of psoriasis. We ought to assess the specific function of IL-36R in keratinocytes for the pathology of Aldara®-induced psoriasis-like skin inflammation. Il36r-/- (KO) and Il36rΔK (DK) mice as well as their littermate controls, respectively Il36r+/+ (WT) and Il36rfl/fl (FL) mice, were challenged with the topical application of Aldara® on one ear during 3 or 7 days. RNASeq was performed on treated (AL) and untreated (CT) ears. Fold change analysis combined with RPKM and RT-qPCR allowed us to identify genes which were specifically regulated by IL-36R signaling in keratinocytes during the course of the treatment. We notably demonstrated that both IL-23 subunits (Il23a and Il12b) fell into this category.
2020-04-23 | GSE143688 | GEO
Project description:In this study we tested interactions between IL-36 and IL-17A in human keratinocytes. 24 hours of IL-36 stimulation in keratinocytes promoted IL-36, IL-17C, and characteristic psoriasis-related molecule expressions in normal human epidermal keratinocytes in dose-dependent manners as measured by mRNA and protein quantification.
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Project description:Keratinocytes isolated from one healthy donor were stimulated in triplicate for 24h with IL-36α, IL-36β or IL-36γ
2017-10-11 | GSE96601 | GEO
Project description:IL-36 cytokines have recently emerged as mediators of inflammation in autoimmune conditions including psoriasis vulgaris (PsV) and generalized pustular psoriasis (GPP). This study used RNA-seq to profile the transcriptome of primary epidermal keratinocytes (KCs) treated with IL-1B, IL-36A, IL-36B or IL-36G. We identified some early IL-1B-specific responses (8 hours post-treatment), but nearly all late IL-1B responses were replicated by IL-36 cytokines (24 hours post-treatment). Type I and II interferon genes exhibited time-dependent response patterns, with early induction (8 hours) followed by no response or repression (24 hours). Altogether, we identified 225 differentially expressed genes (DEGs) with shared responses to all 4 cytokines at both time points (8 + 24 hours). These involved up-regulation of ligands (IL1A, IL1B, IL36G) and activating proteases (CTSS), but also up-regulation of inhibitors such as IL1RN and IL36RN. Shared IL-1B/IL-36 DEGs overlapped significantly with genes altered in PsV and GPP skin lesions, as well as genes near GWAS loci linked to autoimmune and autoinflammatory diseases (e.g., PsV, psoriatic arthritis, IBD, primary biliary cholangitis). Inactivation of MyD88 adapter protein using CRISPR/Cas9 completely abolished expression responses of such DEGs to IL-1B and IL-36G stimulation. These results provide a global view of IL-1B and IL-36 expression responses in epidermal KCs with fine-scale characterization of time-dependent and cytokine-specific response patterns. Our findings support an important role for IL-1B and IL-36 in autoimmune or autoinflammatory conditions and show that MyD88 adaptor protein mediates shared IL-1B/IL-36 responses.
2018-03-04 | GSE109182 | GEO
Project description:Interleukin 23 (IL-23) triggers pathogenic features in pro-inflammatory, IL-17-secreting T cells (Th17 and Tγδ17) that play a key role in the development of inflammatory diseases. However, the IL-23 signaling cascade remains largely undefined. Here we used quantitative phosphoproteomics to characterize IL-23 signaling in primary murine Th17 cells. We quantified 6,888 phosphorylation sites in Th17 cells, and found 168 phosphorylations regulated upom IL-23 stimulation. IL-23 increased the phosphorylation of the myosin regulatory light chain (RLC), an actomyosin contractibility marker, in Th17 and Tγδ cells. IL-23-induced RLC phosphorylation required JAK2 and ROCK catalytic activity, and the study of the IL-23/ROCK axis revealed an unexpected role of IL-23 in the migration of Tγδ17 and Th17 cells. Moreover, pharmacological inhibition of ROCK reduced Tγδ17 recruitment to inflamed skin upon challenge with inflammatory agent Imiquimod. This work: i) provides new insights into phosphorylation networks that control Th17 cells, ii) widely expands the current knowledge on IL-23 signaling, and iii) contributes to the increasing list of immune cells subsets characterized by global phosphoproteomic approaches.
2020-03-25 | PXD016633 | Pride
Project description:IL-36 and IL-17A Cooperatively Induce a Psoriasis-like Gene Expression Response in Human Keratinocytes
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Project description:IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we performed single-cell RNA-seq on an acute LPS mouse model of lung inflammation to provide insights into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. We identified neutrophils as a source of IL-36 which provides a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases.
2021-01-25 | GSE159161 | GEO
Project description:Cryopreserved human PBMCs from six donors were stimulated with anti-CD3/CD28 beads in the presence or absence of 100ng/ml IL-23 for 22 hours. RNA samples were assessed for consistency with a Bioanalyzer (Agilent) and quantified by a Nanodrop® ND 1000 Spectrophotometer (Nanodrop Technologies, USA). Expression array data was quantile normalised, detection above background statistical testing performed, comparison between activated un-stimulated versus activated IL-23 stimulated conditions performed as a paired test using the Illumina Custom differential expression algorithm (all implemented in Illumina BeadStudio GeneExpression Module v3.2). Two sample groups were compared, each with 6 biological replicates. Group 1 was stimulated with CD3CD28 antibody coated beads as a control group for 22hours. Group 2 was stimulated as the control group and treated with IL-23 100ng/ml for the same time period. Keywords: Cytokine Treatment
2009-10-10 | GSE10080 | GEO
Project description:Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of these cytokines is effective for treating psoriasis, IL-12/23 inhibition attenuates Crohn's disease, while IL-17A or IL-17RA inhibition exacerbates disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the mdr1a- /- mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing Treg accumulation. Exacerbation of colitis by IL-17A or IL-17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provides insight into mechanisms underlying exacerbation of Crohn's disease when IL-17A or IL-17RA is inhibited.
2015-08-20 | GSE72212 | GEO
Project description: Not available
| S-EPMC7190273 | biostudies-literature