Dataset Information

DDX5-sIL-36R in keratinocytes controls skin inflammation

ABSTRACT: 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.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yuping Lai

PROVIDER: PXD021379 | iProX | Wed Sep 09 00:00:00 BST 2020

REPOSITORIES: iProX

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Publications

IL-17D-induced inhibition of DDX5 expression in keratinocytes amplifies IL-36R-mediated skin inflammation.

Ni Xinhui X Xu Yi Y Wang Wang W Kong Baida B Ouyang Jian J Chen Jiwei J Yan Man M Wu Yawei Y Chen Qi Q Wang Xinxin X Li Hongquan H Gao Xiaoguang X Guo Hongquan H Cui Lian L Chen Zeyu Z Shi Yuling Y Zhu Ronghui R Li Wei W Shi Tieliu T Wang Lin-Fa LF Huang Jinling J Dong Chen C Lai Yuping Y

Nature immunology 20221021 11

Aberrant RNA splicing in keratinocytes drives inflammatory skin disorders. In the present study, we found that the RNA helicase DDX5 was downregulated in keratinocytes from the inflammatory skin lesions in patients with atopic dermatitis and psoriasis, and that mice with keratinocyte-specific deletion of Ddx5 (Ddx5<sup>∆KC</sup>) were more susceptible to cutaneous inflammation. Inhibition of DDX5 expression in keratinocytes was induced by the cytokine interleukin (IL)-17D through activation of t ...[more]

PMID: 36271146

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Project description:Transcriptional profiling of Homo sapiens inflammatory skin diseases (whole skin biospies): Psoriasis (Pso), vs Atopic Dermatitis (AD) vs Lichen planus (Li), vs Contact Eczema (KE), vs Healthy control (KO) In recent years, different genes and proteins have been highlighted as potential biomarkers for psoriasis, one of the most common inflammatory skin diseases worldwide. However, most of these markers are not psoriasis-specific but also found in other inflammatory disorders. We performed an unsupervised cluster analysis of gene expression profiles in 150 psoriasis patients and other inflammatory skin diseases (atopic dermatitis, lichen planus, contact eczema, and healthy controls). We identified a cluster of IL-17/TNFα-associated genes specifically expressed in psoriasis, among which IL-36γ was the most outstanding marker. In subsequent immunohistological analyses IL-36γ was confirmed to be expressed in psoriasis lesions only. IL-36γ peripheral blood serum levels were found to be closely associated with disease activity, and they decreased after anti-TNFα-treatment. Furthermore, IL-36γ immunohistochemistry was found to be a helpful marker in the histological differential diagnosis between psoriasis and eczema in diagnostically challenging cases. These features highlight IL-36γ as a valuable biomarker in psoriasis patients, both for diagnostic purposes and measurement of disease activity during the clinical course. Furthermore, IL-36γ might also provide a future drug target, due to its potential amplifier role in TNFα- and IL-17 pathways in psoriatic skin inflammation. In recent years, different genes and proteins have been highlighted as potential biomarkers for psoriasis, one of the most common inflammatory skin diseases worldwide. However, most of these markers are not psoriasis-specific but also found in other inflammatory disorders. We performed an unsupervised cluster analysis of gene expression profiles in 150 psoriasis patients and other inflammatory skin diseases (atopic dermatitis, lichen planus, contact eczema, and healthy controls). We identified a cluster of IL-17/TNFα-associated genes specifically expressed in psoriasis, among which IL-36γ was the most outstanding marker. In subsequent immunohistological analyses IL-36γ was confirmed to be expressed in psoriasis lesions only. IL-36γ peripheral blood serum levels were found to be closely associated with disease activity, and they decreased after anti-TNFα-treatment. Furthermore, IL-36γ immunohistochemistry was found to be a helpful marker in the histological differential diagnosis between psoriasis and eczema in diagnostically challenging cases. These features highlight IL-36γ as a valuable biomarker in psoriasis patients, both for diagnostic purposes and measurement of disease activity during the clinical course. Furthermore, IL-36γ might also provide a future drug target, due to its potential amplifier role in TNFα- and IL-17 pathways in psoriatic skin inflammation.

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Dataset Information

DDX5-sIL-36R in keratinocytes controls skin inflammation

Publications

IL-17D-induced inhibition of DDX5 expression in keratinocytes amplifies IL-36R-mediated skin inflammation.

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