GSDME-mediated keratinocyte pyroptosis participates in the pathogenesis of psoriasis by promoting skin inflammation

Yingfei Li; Yi He; Fangyuan Yang; Rongmei Liang; Wenchao Xu; Yehao Li; Jingbo Cheng; Baozhu Liang; Ming Tang; Xingliang Shi; Jian Zhuang; Minshuang Luo; Liuying Li; Ruilin Zhang; Huijuan Liu; Hongyu Jie; Xing Li; Xinai Han; Erwei Sun; Zeqing Zhai

doi:10.1093/bjd/ljae179

GSDME-mediated keratinocyte pyroptosis participates in the pathogenesis of psoriasis by promoting skin inflammation

Br J Dermatol. 2024 Apr 24:ljae179. doi: 10.1093/bjd/ljae179. Online ahead of print.

Authors

Yingfei Li^{1

2

3}, Yi He^{1

2

3}, Fangyuan Yang^{1

2

3}, Rongmei Liang^{1

2

3}, Wenchao Xu^{1

2

3}, Yehao Li^{1

2

3}, Jingbo Cheng^{2

3

4}, Baozhu Liang^{1

2

3}, Ming Tang^{1

2

3}, Xingliang Shi^{1

2

3}, Jian Zhuang^{1

2

3}, Minshuang Luo^{1

2

3}, Liuying Li^{1

2

3}, Ruilin Zhang^{1

2

3}, Huijuan Liu^{1

2

3}, Hongyu Jie^{1

2

3}, Xing Li^{1

2

3}, Xinai Han^{1

2

3}, Erwei Sun^{1

2

3}, Zeqing Zhai^{1

2

3}

Affiliations

¹ Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
² Department of Rheumatology and Immunology, Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.
³ Department of Clinical Immunology, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
⁴ Department of Anesthesiology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Province, China.

PMID: 38655652
DOI: 10.1093/bjd/ljae179

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.