PIEZO1 promotes psoriasis-like skin inflammation in mice via NF-κB/IL-17 signaling pathway activation
Wen Li, Kan Ze, Xufeng He, Lili Yang, Huimin Zhang, Weian Yuan, Wuqing Wang
Abstract
BACKGROUND: Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferative keratinocytes and an altered immune response. PIEZO1, a mechanically activated ion channel, has been implicated in various cellular processes, but its role in psoriasis pathogenesis remains unclear. METHODS: We examined PIEZO1 expression in skin samples from psoriatic patients and healthy individuals using western blot, immunohistochemistry, and mRNA expression analyses. Subsequently, we employed PIEZO1 knock-out (KO) mice to establish imiquimod (IMQ)-induced psoriasiform models for in vivo experiments. Additionally, we conducted in vitro experiments with PIEZO1-silenced human keratinocytes (HaCaT cells) to investigate the impact on keratinocyte function and the expression of inflammatory cytokines. RESULTS: PIEZO1 expression was significantly upregulated in the basal layer of psoriatic lesions compared to healthy controls. In vivo, PIEZO1 KO mice showed attenuated psoriasis-like symptoms, reduced keratinocyte proliferation, inflammatory cell infiltration, and less Th17 cells compared to wild-type mice. Loss of PIEZO1 in vitro inhibited keratinocyte proliferation and migration, while inducing apoptosis. Transcriptome sequencing and subsequent analyses revealed that PIEZO1 knockdown modulates the NF-kB signaling pathway and associated inflammatory genes. The in vitro activation of NF-kB signaling was diminished by PIEZO1 silencing in keratinocytes, resulting in decreased inflammatory cytokine and chemokine expression. Furthermore, PIEZO1 facilitated keratinocyte-mediated CD4 + T cell differentiation into Th17 cells, a key pathogenic factor in psoriasis. CONCLUSION: This study highlights the critical role of PIEZO1 in psoriatic skin inflammation and suggests that PIEZO1 may serve as a novel therapeutic target for psoriasis treatment. Our findings reveal that PIEZO1 modulates keratinocyte proliferation, immune cell infiltration, and T cell differentiation through the NF-kB signaling pathway, contributing to the complex pathophysiology of psoriasis.