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IL-36 signaling in keratinocytes controls early IL-23 production in Aldara®-induced skin inflammation in mice

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE143688 | GEO | 2020/04/23

REPOSITORIES: GEO

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IL-36 signaling in keratinocytes controls early IL-23 production in Aldara®-induced skin inflammation in mice

Project description:IL-36 signaling in keratinocytes controls early IL-23 production in Aldara®-induced skin inflammation in mice

| PRJNA601253 | ENA

Single-cell transcriptomics reveals prominent expression of IL-14, IL-18 and IL-32 in psoriasis

Project description:Several different immune-activated cell types with particular cytokine patterns are identified such as keratinocytes, T helper cells, cytotoxic T cells, dendritic cells, macrophages, fibroblasts, and endothelial cells. The expression of well-known pathogenic factors such as TNF-α, IL-8 (CXCL8), L-23 and IL-17 is confirmed in different inflammatory cells. Furthermore, IL-14 (TXLNA; alpha-taxilin), IL-18 and IL-32 are identified as less well-known, and putative new pathogenic factors. Prominent expression of IL-18 is found in keratinocytes, macrophages and Langerhans cells, prominent IL-32 is found in T helper and regulatory T cells, IL-14 is mainly expressed by keratinocytes, fibroblasts and macrophages. Validation of gene expression is performed by ISH of human skin samples. In a murine model of psoriasis, IL-14 and IL-18 are significantly higher expressed in psoriasis-like skin lesions than in normal skin. In an analysis of serum samples from psoriasis patients, IL-18 shows higher expression in psoriasis patients compared to controls, and serum levels in psoriasis responded to treatment with IL-17 inhibitors.

2023-08-14 | GSE221648 | GEO

Human keratinocytes stimulated with IL-17C

Project description:IL-17C is important for the pathogenesis of inflammatory diseases such as IBD and psoriasis. We found that IL-17C is highly induced in a murine model of psoriasis. Recent results suggest that IL-17C can target epithelial cells that express both IL-17RA and IL-17RE receptor chains. Here we identify genes induced in response to IL-17C treatment of human keratinocytes to provide the tools for dissection of the IL-17C signaling pathway. Human keratinocytes, HEKn, were incubated in the absence (n = 3) and presence (n = 5) of 500 ng/ml recombinant human IL-17C for 3 and 24 hours. Whole RNA was isolated via RNeasy kit (Qiagen).

2011-10-11 | E-GEOD-32620 | biostudies-arrayexpress

IL-36 and IL-17A Cooperatively Induce a Psoriasis-like Gene Expression Response in Human Keratinocytes

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.

2021-12-31 | GSE160904 | GEO

Multiple IL-17 family cytokines signaling through IL-17RA drive inflammatory pathways in psoriasis

Project description:The IL-23/IL-17 immune axis is of central importance in psoriasis. However, the contribution of IL-17 family cytokines other than IL-17A to drive skin inflammation in psoriasis has not been fully established. To further elucidate the role of individual IL-17 family cytokines in psoriasis, we investigated their expression and localization in psoriasis skin at the mRNA and protein level. Moreover, we investigated the gene expression signatures induced by individual IL-17 family cytokines in human skin ex vivo as well as modulation of responses induced by the combination of IL-17 family cytokines in human keratinocytes by brodalumab, a human monoclonal antibody targeting the IL-17RA, versus the IL-17A blocking antibody ixekizumab. We demonstrate that IL-17A, IL-17AF, IL-17F and IL-17C are expressed at increased levels in psoriasis lesional skin and induce inflammatory gene expression signatures in human skin ex vivo that correlate with those observed in psoriasis. Furthermore, we show that brodalumab, in contrast to ixekizumab, fully blocks gene expression responses induced by the combination of IL-17A, IL-17AF, IL-17F and IL-17C in human keratinocytes. These findings suggest that inhibition of several IL-17 family cytokines, e.g. by targeting of the IL-17RA receptor, could be a favored mechanism to obtain a profound suppression of the inflammatory processes in psoriasis and thereby achieve high levels of skin clearance and sustained efficacy in patients with psoriasis.

2021-04-07 | GSE158448 | GEO

IL-17A plays a central role in the expression of psoriasis signature genes through induction of IkappaB-zeta in keratinocytes

Project description:In psoriasis lesions, a diverse mixture of cytokines is upregulated which influence each other generating a complex inflammatory situation. Although this is the case, the inhibition of Interleukin-17A (IL-17A) alone showed unprecedented clinical results in patients, indicating that IL-17A is a critical inducer of psoriasis pathogenesis. To elucidate IL-17A-driven keratinocyte-intrinsic signaling pathways, we treated monolayers of normal human epidermal keratinocytes in vitro with a mixture of 6 cytokines (IL-17A, TNF-a, IL-17C, IL-22, IL-36g and IFN-g) involved in psoriasis, to mimic the inflammatory milieu in psoriasis lesions. Microarray and gene set enrichment analysis revealed that this cytokine mixture induced similar gene expression changes with the previous transcriptome studies using psoriasis lesions. Importantly, we identified a set of IL-17A-regulated genes in keratinocytes, which recapitulate typical psoriasis genes exemplified by DEFB4A, S100A7, IL19 and CSF3, based on differences in the expression profiles of cells stimulated with 6 cytokines versus cells stimulated with only 5 cytokines lacking IL-17A. Furthermore a specific IL-17A-induced gene, NFKBIZ, which encodes IkappaB-zeta, a transcriptional regulator for NF-kappaB, was demonstrated to have a significant role for IL-17A-induced gene expression. Thus, we present novel in vitro data from normal human keratinocytes that would help elucidating the IL-17A-driven keratinocyte activation in psoriasis. Cytokine mixture-induced gene expression in primary normal human epidermal keratinocytes (NHEKs) was measured at 24 hours after exposure. NHEKs were exposed to the combination of selected six cytokines (IL-17A: 100 ng/ml, TNF-a: 10 ng/ml, IFN-g: 10 ng/ml, IL-17C: 100 ng/ml, IL-22: 100 ng/ml, IL-36g: 500 ng/ml) , or to the different combinations of five of the six cytokines (in total, 7 different treatments and one untreated control). No replicate experiments were conducted.

2016-03-08 | E-GEOD-77719 | biostudies-arrayexpress

Induction of alternative proinflammatory cytokines accounts for sustained psoriasiform skin inflammation in IL-17C+IL-6KO mice [array]

Project description:IL-6 inhibition has been unsuccessful in treating psoriasis, despite high levels of tissue and serum IL-6 in patients. Additionally, de novo psoriasis onset has been reported following IL-6 blockade in rheumatoid arthritis patients. To explore mechanisms underlying these clinical observations, we backcrossed an established psoriasiform mouse model (IL-17C+ mice) with IL-6 deficient mice (IL-17C+KO) and examined the cutaneous phenotype. IL-17C+KO mice initially exhibited decreased skin inflammation, however this decrease was transient and reversed rapidly, concomitant with increases in skin Tnf, Il36α/β/γ, Il24, epigen and S100a8/a9 to levels higher than those found in IL-17C+ mice. Comparison of IL-17C+ and IL-17C+KO mouse skin transcriptomes with that of human psoriasis skin, revealed significant correlation among transcripts of psoriasis patient skin and IL-17C+KO mouse skin, and confirmed an exacerbation of the inflammatory signature in IL-17C+KO mice that aligns closely with human psoriasis. Transcriptional analyses of IL-17C+ and IL-17C+KO primary keratinocytes confirmed increased expression of proinflammatory molecules, suggesting that in the absence of IL-6, keratinocytes increase production of numerous additional proinflammatory cytokines. These preclinical findings may provide insight into why arthritis patients being treated with IL-6 inhibitors develop new onset psoriasis and why IL-6 blockade for the treatment of psoriasis has not been clinically effective.

2017-08-01 | GSE86139 | GEO

Induction of alternative proinflammatory cytokines accounts for sustained psoriasiform skin inflammation in IL-17C+IL-6KO mice [RNA-Seq]

2017-08-01 | GSE85967 | GEO

Human keratinocytes stimulated with IL-17C

2011-10-12 | GSE32620 | GEO

IL-37 negatively regulates IL-33 expression in human keratinocytes

Project description:Interleukin (IL)-37 suppresses systemic and local inflammation. It is expressed in the epidermis, the external layer of the skin, and is decreased in inflammatory skin diseases including atopic dermatitis (AD) and psoriasis. Therefore, an agent applied topically on the skin that can increase IL-37 could be promising for treating AD and psoriasis; however, the mechanism regulating IL-37 remains largely unknown. Given that IL-37 expression is induced in differentiated keratinocytes, a major component of the epidermis, and that activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, promotes keratinocyte differentiation, we hypothesized that AHR might be involved in the IL-37 expression in human keratinocytes. We analyzed normal epidermal human keratinocytes (NHEKs) treated with tapinarof and Galactomyces fermentation filtrate (GFF), which are potent AHR modulators. We found that tapinarof and GFF upregulated IL-37 in NHEKs, which was canceled by the knockdown of AHR using siRNA transfection, indicating that AHR mediates IL-37 expression in NHEKs. Furthermore, we found that the knockdown of IL-37 resulted in the upregulation of IL-33, an alarmin cytokine with crucial roles in the pathogenesis of AD and psoriasis. These findings suggest that IL-37 negatively regulates IL-33 expression in NHEKs. Finally, we examined whether tapinarof and GFF treatment modulates IL-33 expression in NHEKs. Such treatment inhibited IL-33 expression, which was partially reversed by the knockdown of either AHR or IL-37. Taken together, our findings provide the first evidence that tapinarof and GFF could have potential to prevent IL-33-overexpressing disorders such as AD and psoriasis via the AHR/IL-37 axis.

2021-12-31 | GSE181089 | GEO

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