Piezo1 exacerbates psoriasis by promoting macrophage M1 polarization and inhibits autophagy via activating PI3K/AKT signaling pathway
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Published on: September 20, 2024
Xiaoke Liu1,2, Simo Du3, Yuxiong Jiang4,5
1Department of Dermatology, Tenth People's Hospital Affiliated to Tongji University, Tongji University School of Medicine, No. 301 Middle Yanchang Road, Shanghai, 200072, China. liuxiaoke2025@163.com.
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.
Insights
The Piezo1 protein amplifies skin inflammation in psoriasis by blocking autophagy and activating the PI3K/AKT pathway, promoting M1 macrophage polarization. This leads to increased disease severity.
Area of Science:
- Dermatology
- Immunology
- Cell Biology
Background:
- Psoriasis is a chronic inflammatory skin disease.
- Macrophage polarization and autophagy are key processes in psoriasis pathogenesis.
- The role of Piezo1 in psoriasis remains unclear.
Purpose of the Study:
- To investigate the role of Piezo1 in macrophage polarization and autophagy in psoriasis.
- To determine if the PI3K/AKT pathway mediates these effects.
Main Methods:
- Utilized wild-type and Piezo1-knockout mice treated with imiquimod.
- Employed shRNA for Piezo1 silencing and pharmacological agents for autophagy modulation.
- Conducted HE staining, immunohistochemistry, RNA-seq, Western blot, immunofluorescence, flow cytometry, and ELISA for analysis.
Main Results:
- Piezo1 expression was significantly upregulated in psoriatic lesions.
- Piezo1 knockout attenuated disease severity, increased autophagy (LC3-II/I ratio), reduced p62, and decreased inflammatory cytokines.
- Macrophages shifted from M1 to M2 phenotype, suppressing keratinocyte proliferation and promoting apoptosis.
- RNA-seq identified the PI3K/AKT pathway as a key mediator.
Conclusions:
- Piezo1 inhibition of autophagy and activation of PI3K/AKT signaling drives M1 macrophage polarization.
- Piezo1 exacerbates cutaneous inflammation in psoriasis.
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