Piezo1-specific deletion in macrophage attenuates radiation-induced lung injury progression in mice.

BACKGROUND

Macrophages play a crucial role in the inflammation and wound repair processes of radiation-induced lung injury (RILI). The mechanosensitive ion channel Piezo1 is upregulated during these inflammatory and wound repair processes. However, the involvement of macrophage Piezo1 in the pathogenesis of RILI remains unclear. This study aims to elucidate the regulatory role of Piezo1 in the injury and repair process in RILI and to investigate the underlying mechanisms.

METHODS

We established Myeloid-specific knockout of Piezo1 (Piezo1∆ LysM) mice, and the mice were subjected to total-chest irradiation (15 Gy) to simulate the clinical situation. Additionally, LPS treatment was performed on bone marrow-derived macrophages in vitro. The expression of Piezo1 in RILI was analyzed using the GEO database. In Piezo1fl/fl and Piezo1∆LysM mice, Piezo1 and EMT markers expression were detected by immunofluorescence, RT-qPCR, and Western blotting, the concentration of inflammatory factors by ELISA, alveolar macrophages were sorted by flow cytometry. In vivo and in vitro experiments involving Myeloid Piezo1 knockout and activation of Piezo1 with the specific agonist Yoda1 were conducted to observe the effects on lung injury.

RESULTS

Our findings revealed that Piezo1 is upregulated in lung macrophages in mice with RILI. Myeloid Piezo1 knockout provided protective effects in mice with RILI. Myeloid-specific Piezo1 deficiency alleviates inflammatory responses, manifested by the alleviation of inflammatory damage in lung tissue, changes in the concentrations of related inflammatory factors. Simultaneously, this deficiency reduces radiation-induced pulmonary fibrosis, with improved fibrosis indicators and decreased expression of EMT markers. Moreover, myeloid Piezo1 knockout inhibited paracrine-induced EMT of BEAS-2B cells by alveolar macrophages, and reduced macrophage recruitment. Mechanistically, the regulatory effects of Piezo1 on lung macrophages were activated Ca2+-dependent calpain signaling, which critically upregulated MCP-1/CCR2/NF-κB and endoplasmic reticulum (ER) stress-induced ATF6/CHOP signaling axis.

CONCLUSION

Our findings revealed the important function of Piezo1 in RILI, knockout or pharmacological inhibition of Piezo1may serve as a promising strategy for treating RILI.