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Gasdermin E-mediated keratinocyte pyroptosis participates in the pathogenesis of psoriasis by promoting skin inflammation.
- Source :
-
British Journal of Dermatology . Sep2024, Vol. 191 Issue 3, p385-396. 12p. - Publication Year :
- 2024
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Abstract
- Background Psoriasis is a common chronic inflammatory disease with an unclear aetiology. Keratinocytes in psoriasis are susceptible to exogenous triggers that induce inflammatory cell death. Objectives To investigate whether gasdermin E (GSDME)-mediated pyroptosis in keratinocytes contributes to the pathogenesis of psoriasis. Methods Skin samples from patients with psoriasis and from healthy controls were collected to evaluate the expression of GSDME, cleaved caspase-3 and inflammatory factors. We then analysed the data series GSE41662 to further compare the expression of GSDME between lesional and nonlesional skin samples in those with psoriasis. In vivo, a caspase-3 inhibitor and GSDME-deficient mice (Gsdme–/–) were used to block caspase-3/GSDME activation in an imiquimod-induced psoriasis model. Skin inflammation, disease severity and pyroptosis-related proteins were analysed. In vitro , tumour necrosis factor (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 was upregulated in psoriasis lesions vs. normal skin. High levels of inflammatory cytokines such as interleukin (IL)-1β, IL-6 and TNF-α were also found in psoriasis lesions. In mice in the Gsdme –/– and caspase-3 inhibitor groups, the severity of skin inflammation was attenuated and GSDME and cleaved caspase-3 levels decreased after imiquimod treatment. Similarly, IL-1β, IL-6 and TNF-α expression was decreased in the 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. Conclusions Our study provides a novel explanation of TNF-α/caspase-3/GSDME-mediated keratinocyte pyroptosis in the initiation and -acceleration of skin inflammation and the progression of psoriasis. [ABSTRACT FROM AUTHOR]
- Subjects :
- *SKIN inflammation
*CELL death
*ETIOLOGY of diseases
*PYROPTOSIS
*CASPASES
Subjects
Details
- Language :
- English
- ISSN :
- 00070963
- Volume :
- 191
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- British Journal of Dermatology
- Publication Type :
- Academic Journal
- Accession number :
- 179059391
- Full Text :
- https://doi.org/10.1093/bjd/ljae179