PIEZO1 promotes psoriasis-like skin inflammation in mice via NF-κB/IL-17 signaling pathway activation.

backgroundPsoriasis 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.

methodsWe 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.

resultsPIEZO1 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.

conclusionThis 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.