Piezo1 exacerbates psoriasis by promoting macrophage M1 polarization and inhibits autophagy via activating PI3K/AKT signaling pathway.

OBJECTIVE AND

DESIGN

This study was designed to delineate how Piezo1 orchestrates macrophage polarization and autophagy in psoriasis and to determine whether the PI3K/AKT axis mediates these effects.

MATERIAL OR SUBJECTS: Wild-type and Piezo1-knockout C57BL/6 mice were obtained from Vital River; human THP-1 monocytes and HaCaT keratinocytes were supplied by the Cell Bank of the Chinese Academy of Sciences.

TREATMENT: Imiquimod was applied topically for six consecutive days; Piezo1 was silenced with shRNA, and autophagy was pharmacologically inhibited (10 mM 3-MA) or activated (200 nM rapamycin).

METHODS

HE staining, immunohistochemistry and RNA-seq were performed in vivo. Western blot, immunofluorescence and flow cytometry quantified LC3-II/I, p62, PI3K/AKT proteins and CD86/CD206; cytokines were measured by ELISA.

RESULTS

Piezo1 expression was significantly elevated in psoriatic lesions (P < 0.01). Genetic deletion of Piezo1 markedly attenuated disease severity, accompanied by an increased LC3-II/I ratio, reduced p62 accumulation, and a pronounced decline in inflammatory cytokine levels. Macrophages shifted from M1 to M2, suppressing keratinocyte proliferation and promoting apoptosis. RNA-seq confirmed the PI3K/AKT pathway as the key mediator.

CONCLUSIONS

Piezo1 amplifies cutaneous inflammation by inhibiting autophagy and activating PI3K/AKT signalling to drive M1 macrophage polarization.