作者
Yingfei Li,Yingfei Li,Yingfei Li,Yi He,Yi He,Yi He,Fangyuan Yang,Fangyuan Yang,Fangyuan Yang,Liang Ran,Liang Ran,Liang Ran,Wenchao Xu,Wenchao Xu,Wenchao Xu,Yehao Li,Yehao Li,Yehao Li,Jack C. Y. Cheng,Jack C. Y. Cheng,Jack C. Y. Cheng,Bo Liang,Bo Liang,Bo Liang,Ming Tang,Ming Tang,Ming Tang,Xingliang Shi,Xingliang Shi,Xingliang Shi,Jian Zhuang,Jian Zhuang,Jian Zhuang,Minshuang Luo,Minshuang Luo,Minshuang Luo,Liuying Li,Liuying Li,Liuying Li,Ruilin Zhang,Ruilin Zhang,Ruilin Zhang,Huijuan Liu,Huijuan Liu,Huijuan Liu,Hongyu Jie,Jie Hou,Jie Hou,Xing Li,Xing Li,Xing Li,Xinai Han,Xinai Han,Xinai Han,Erwei Sun,Erwei Sun,Erwei Sun,Zeqing Zhai,Zeqing Zhai,Zeqing Zhai
摘要
Abstract Objective Psoriasis is a common, chronic inflammatory disease with unclear etiology. Keratinocytes in psoriasis are susceptible to exogenous triggers that induce inflammatory cell death. This study investigated whether GSDME-mediated pyroptosis in keratinocytes contributes to the pathogenesis of psoriasis. Methods Skin samples from patients with psoriasis and healthy controls were collected to evaluate the expression of GSDME, cleaved-caspase-3, and inflammatory factors. We then analyzed the data series, GSE41662, to further compare the expression of GSDME between lesional and non-lesional skin samples in those with psoriasis. In vivo, caspase-3 inhibitor and GSDME deficiency mice (Gsdme-/-) were applied to block caspase-3/GSDME activation in the imiquimod-induced psoriasis model. Skin inflammation, disease severity, and pyroptosis-related proteins were analyzed. In vitro, tumor necrosis factor-α (TNF-α)-induced caspase-3/GSDME-mediated pyroptosis in the HACAT cell line was explored. Results Our analysis of the GSE41662 data series found that GSDME were upregulated in psoriasis lesions, compared to normal skin. High levels of inflammatory cytokines such as IL-1β, IL-6, and TNF-α were also found in psoriasis lesions. In mice of Gsdme-/- and caspase-3 inhibitor groups, the severity of skin inflammation was attenuated, and GSDME and C-caspase-3 levels decreased after imiquimod treatment. Similarly, IL-1β, IL-6, and TNF-α were decreased in Gsdme-/- and caspase-3 inhibitor groups. In vitro, TNF-α induced HACAT cell pyroptosis through caspase-3/GSDME pathway activation, which was suppressed by blocking caspase-3 or silencing GSDME. Conclusion Our study provides a novel explanation that TNF-α/caspase-3/GSDME-mediated keratinocyte pyroptosis is highly responsible for the initiation and acceleration of skin inflammation and progression of psoriasis.