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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE85967 | GEO | 2017/08/01

SECONDARY ACCESSION(S): PRJNA339850

REPOSITORIES: GEO

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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

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

Human keratinocytes stimulated with IL-17C

2011-10-12 | GSE32620 | 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-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

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

Single-cell genomics segregate different transcriptomic impacts of anti-IL-17A blockade on type 17 T-cells and regulatory immune cells in psoriasis skin

Project description:Durable psoriasis improvement has been reported in a subset of psoriasis patients after treatment withdrawal of biologics blocking IL-23/Type 17 T-cell (T17) autoimmune axis. However, it is not well understood if systemic blockade of the IL-23/T17 axis promotes immune tolerance in psoriasis skin. The purpose of the study was to find translational evidence that systemic IL-17A blockade promotes regulatory transcriptome modification in human psoriasis skin immune cell subsets. We analyzed human psoriasis lesional skin 6 mm punch biopsy tissues before and after systemic IL-17A blockade using the muti-genomics approach integrating immune cell-enriched scRNA-seq (n = 18), microarray (n = 61), and immunohistochemistry (n = 61) with repository normal control skin immune cell-enriched scRNA-seq (n = 10) and microarray (n = 8) data. For the T17 axis transcriptome, systemic IL-17A blockade depleted 100% of IL17A + T-cells and 95% of IL17F + T-cells in psoriasis skin. The expression of IL23A in DC subsets was also downregulated by IL-17A blockade. The expression of IL-17-driven inflammatory mediators (IL36G, S100A8, DEFB4A, and DEFB4B) in suprabasal keratinocytes was correlated with psoriasis severity and was downregulated by IL-17A blockade. For the regulatory DC transcriptome, the proportion of regulatory semimature DCs expressing regulatory DC markers of BDCA-3 (THBD) and DCIR (CLEC4A) was increased in posttreatment psoriasis lesional skin compared to pretreatment psoriasis lesional skin. In addition, IL-17A blockade induced higher expression of CD1C and CD14, which are markers of CD1c+ CD14+ dendritic cell (DC) subset that suppresses antigen-specific T-cell responses, in posttreatment regulatory semimature DCs compared to pretreatment regulatory semimature DCs. In conclusion, systemic IL-17A inhibition not only blocks the entire IL-23/T17 cell axis but also promotes regulatory gene expression in regulatory DCs in human psoriasis skin.

2023-09-04 | GSE183047 | GEO

IL-12 regulates type 3 immunity through interfollicular keratinocytes in psoriasiform inflammation

Project description:Psoriasis is a chronic inflammatory skin disorder underpinned by dysregulated cytokine signaling. Drugs neutralizing the common p40 subunit of IL-12 and IL-23 represented a therapeutic breakthrough; however, new drugs that block the IL-23p19 subunit and spare IL-12 are more effective, suggesting a regulatory function of IL-12. In order to pinpoint the cell type and underlying mechanism of IL-12 mediated immune-regulation in psoriasis we generated a conditional Il12rb2-knockout (KO)/reporter mouse strain. We detected Il12rb2 expression in T cells and a specific subset of interfollicular (IF) keratinocytes. Analysis of scRNAseq data from psoriasis patients confirmed this expression pattern in the human skin. Mechanistically, deletion of Il12rb2 in the keratinocyte compartment led to exacerbated psoriasiform inflammation. Protective IL-12 signaling blocked the hyperproliferation of keratinocytes, maintained skin barrier integrity, and, importantly, diminished disease-driving IL-23/type 3 immune circuits. Collectively, we provide a potential explanation for the superior efficacy of IL-23p19 inhibitors in psoriasis and describe an unperceived role of IL-12 in maintaining skin epithelial cell homeostasis.

2021-08-03 | GSE163700 | GEO

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

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

DDX5-sIL-36R in keratinocytes controls skin inflammation

Project description:The DEAD-box (DDX) proteins function in diverse cellular processes including RNA alternative splicing, and are linked to immune-mediated diseases. However, little is known about the roles of DDXs in skin inflammatory diseases. Here, we show that DDX5, one of the founding members of the DDX RNA helicase family, controls skin inflammation and participates in the pathogenesis of psoriasis via regulating IL-36R pre-mRNA splicing. We found that both mRNA and protein of DDX5 are decreased in lesional skin from patients with psoriasis and psoriasis-like mice, and that mice with keratinocyte-specific ablation of DDX5 spontaneously develop psoriasis-like phenotypes. Mechanistically, DDX5 complexes with serine/arginine-rich splicing factor 1(SRSF1) to typically regulate IL-36R pre-mRNA splicing in keratinocytes, which generates mRNAs encoding full-length IL-36R and a previously unknown soluble form of IL-36R (sIL-36R). sIL-36R controls IL-36/IL-36R signaling by competing with IL-36R for IL-36γ ligation. The reduction or deficiency of DDX5 leads to IL-36R pre-mRNA splicing preferring to the generation of IL-36R but not sIL-36R, thereby selectively amplifying inflammatory responses of keratinocytes to IL-36γ and then aggravating cutaneous inflammation in psoriasis. Genetic restoration or intradermal administration of sIL-36R in psoriasis-like mice suppresses IL-36R signaling and alleviates the disease phenotype of psoriasis. Altogether, these data reveal a pathogenic role of DDX5 during psoriasis, and provide mechanistic insights into the regulation of IL-36R splicing and its impact on psoriasis development.

2020-09-09 | PXD021379 |

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