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RIPK3 promotes skin inflammation by enhancing IL-36α signaling and necroptosis in keratinocytes

文献类型：期刊论文

作者Li, Qing-qing3,4; Yang, Tao2,3; Ren, Jin-jin3,4; Hui, Zhi-zhen1; Lei, Shu-yue2,3; Feng, Chun-lan3; Yang, Xiao-qian3; Tang, Wei1,2,3,4
刊名CELL DEATH & DISEASE
出版日期2025-10-24
卷号16期号:1页码:13
ISSN号2041-4889
DOI10.1038/s41419-025-08096-9
通讯作者Tang, Wei(tangwei@simm.ac.cn)
英文摘要Psoriasis is a chronic inflammatory skin disease characterized by complex pathogenesis involving multiple factors. Keratinocytes, as key structural components, play a critical role in immune regulation and contribute to disease progression through interactions with various immune cells. Receptor-interacting protein kinase 3 (RIPK3) is well-known for its role in necroptosis, acting alongside RIPK1 and mixed-lineage kinase domain-like (MLKL). While studies have shown that inhibitors of necroptosis could alleviate psoriasis-like skin inflammation, direct genetic evidence of RIPK3 is lacking. Furthermore, recent studies have highlighted RIPK3's independent biological functions beyond necroptosis, yet its pathological role in inflammatory skin disease remains poorly understood. This study aimed to elucidate the pathological role of RIPK3 in the progression of skin inflammation, particularly in keratinocytes. We demonstrated that RIPK3 expression was significantly upregulated in psoriasis patients and mice with imiquimod (IMQ)-induced skin inflammation. Importantly, keratinocyte-specific knockout of RIPK3 using gene-editing tools significantly alleviated IMQ-induced skin inflammation in mice. Interestingly, the absence of RIPK3 not only inhibited necroptosis and associated inflammatory responses but also significantly reduced interleukin-36 alpha (IL-36 alpha) expression in keratinocytes. IL-36 alpha, known to drive skin inflammation, promote immune cell recruitment, and disrupt the epidermal barrier, is a critical mediator of inflammatory skin disease pathogenesis. Further investigation using MLKL-knockout mice and keratinocytes revealed that RIPK3 regulates the IL-36 alpha/NF-kappa B signaling axis through an MLKL-independent mechanism. Collectively, our findings uncover a dual pathogenic role for RIPK3 in skin inflammation: promoting inflammation through both canonical necroptosis and a distinct, non-necroptotic pathway that drives IL-36 alpha activation. These insights not only identify RIPK3 as a potential therapeutic target for psoriasis-like skin inflammation but also uncover its previously unappreciated roles in inflammatory diseases beyond necroptosis.
WOS关键词KINASE DOMAIN-LIKE ; PROTEIN ; PSORIASIS ; TNF
资助项目National Natural Science Foundation of China (National Science Foundation of China)[XDB1060000] ; Strategic Priority Research Program of the Chinese Academy of Sciences[20JC1418000] ; Science and Technology Commission of Shanghai Municipality[82173822] ; National Natural Science Foundation of China
WOS研究方向Cell Biology
语种英语
WOS记录号WOS:001599599800009
出版者SPRINGERNATURE
源URL[http://119.78.100.183/handle/2S10ELR8/320475]  
专题中国科学院上海药物研究所
通讯作者Tang, Wei
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
2.Univ Chinese Acad Sci, Sch Pharm, Beijing, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai, Peoples R China
4.Anhui Med Univ, Anhui Collaborat Innovat Ctr Antiinflammat & Immun, Key Lab Antiinflammat & Immune Med, Inst Clin Pharmacol,Minist Educ, Hefei, Peoples R China
推荐引用方式
GB/T 7714		 Li, Qing-qing,Yang, Tao,Ren, Jin-jin,et al. RIPK3 promotes skin inflammation by enhancing IL-36α signaling and necroptosis in keratinocytes[J]. CELL DEATH & DISEASE,2025,16(1):13.
APA Li, Qing-qing.,Yang, Tao.,Ren, Jin-jin.,Hui, Zhi-zhen.,Lei, Shu-yue.,...&Tang, Wei.(2025).RIPK3 promotes skin inflammation by enhancing IL-36α signaling and necroptosis in keratinocytes.CELL DEATH & DISEASE,16(1),13.
MLA Li, Qing-qing,et al."RIPK3 promotes skin inflammation by enhancing IL-36α signaling and necroptosis in keratinocytes".CELL DEATH & DISEASE 16.1(2025):13.

入库方式： OAI收割

来源：上海药物研究所

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