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

被引：50

作者：

Ni, Xinhui ^{[1
]}

Xu, Yi ^{[1
]}

Wang, Wang ^{[1
]}

Kong, Baida ^{[1
]}

Ouyang, Jian ^{[1
]}

Chen, Jiwei ^{[1
]}

Yan, Man ^{[1
]}

Wu, Yawei ^{[1
]}

Chen, Qi ^{[1
]}

Wang, Xinxin ^{[1
]}

Li, Hongquan ^{[1
]}

Gao, Xiaoguang ^{[1
]}

Guo, Hongquan ^{[1
]}

Cui, Lian ^{[2
]}

Chen, Zeyu ^{[2
]}

Shi, Yuling ^{[2
,3
]}

Zhu, Ronghui ^{[4
]}

Li, Wei ^{[4
]}

Shi, Tieliu ^{[1
]}

Wang, Lin-Fa ^{[5
,6
]}

Huang, Jinling ^{[7
,8
]}

Dong, Chen ^{[7
,8
,9
]}

Lai, Yuping ^{[1
]}

机构：

[1] East China Normal Univ, Shanghai Frontiers Sci Ctr Genome Editing & Cell, Shanghai Key Lab Regulatory Biol, Sch Life Sci, Shanghai, Peoples R China

[2] Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Dermatol, Shanghai, Peoples R China

[3] Tongji Univ, Sch Med, Shanghai Skin Dis Hosp, Shanghai, Peoples R China

[4] Fudan Univ, Huashan Hosp, Dept Dermatol, Shanghai, Peoples R China

[5] Duke NUS Grad Med Sch, Emerging Infect Dis Program, Singapore, Singapore

[6] Singhlth Duke NUS Global Hlth Inst, Singapore, Singapore

[7] Tsinghua Univ, Inst Immunol, Beijing, Peoples R China

[8] Tsinghua Univ, Sch Med, Beijing, Peoples R China

[9] Shanghai Jiao Tong Univ, Sch Med, Affiliated Renji Hosp, Shanghai Immune Therapy Inst, Shanghai, Peoples R China

来源：

NATURE IMMUNOLOGY | 2022年 / 23卷 / 11期

基金：

中国国家自然科学基金;

关键词：

ATOPIC-DERMATITIS; IL-17; FAMILY; PIVOTAL ROLE; PSORIASIS; RESPONSES; INSIGHTS; HEALTH; CELLS; SITE;

D O I：

10.1038/s41590-022-01339-3

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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( increment KC)) were more susceptible to cutaneous inflammation. Inhibition of DDX5 expression in keratinocytes was induced by the cytokine interleukin (IL)-17D through activation of the CD93-p38 MAPK-AKT-SMAD2/3 signaling pathway and led to pre-messenger RNA splicing events that favored the production of membrane-bound, intact IL-36 receptor (IL-36R) at the expense of soluble IL-36R (sIL-36R) and to the selective amplification of IL-36R-mediated inflammatory responses and cutaneous inflammation. Restoration of sIL-36R in Ddx5( increment KC) mice with experimental atopic dermatitis or psoriasis suppressed skin inflammation and alleviated the disease phenotypes. These findings indicate that IL-17D modulation of DDX5 expression controls inflammation in keratinocytes during inflammatory skin diseases. Lai and colleagues show that the RNA helicase DDX5 mediates the alternative splicing of the IL-36R mRNA in keratinocytes and modulates skin inflammation downstream of IL-17D signaling.

引用

页码：1577 / +

页数：30

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