Gasdermin D-mediated neutrophil pyroptosis drives inflammation in psoriasis.

Abstract

Psoriasis is a multifactorial immune-mediated inflammatory disease. Its pathogenesis involves abnormal accumulation of neutrophils and T-cell-related abnormalities. Pyroptosis is a type of regulated cell death associated with innate immunity, but its role in psoriasis is unclear. In this study, we found that <i>gasdermin D (GSDMD</i>) is higher in human psoriatic skin than that in normal skin, and in imiquimod-induced psoriasis-like mouse skin, the expression of <i>Gsdmd</i> was most significantly altered in neutrophils and <i>Il1b</i> was also mainly expressed in neutrophils. Immunohistochemical staining of serial sections of skin lesions from psoriasis patients and healthy control also showed that GSDMD expression is higher in psoriasis lesion, especially in neutrophils. <i>Gsdmd</i> deficiency mitigates psoriasis-like inflammation in mice. GSDMD in neutrophils contributes to psoriasis-like inflammation, while <i>Gsdmd</i> depletion in neutrophils attenuates the development of skin inflammation in psoriasis and reduces the release of the inflammatory cytokines. We found that neutrophil pyroptosis is involved in and contributes to psoriasis inflammation, which provides new insights into the treatment of psoriasis by targeting neutrophil pyroptosis.