Myeloid Piezo1 improves inflammation resolution and phagocytosis in acute liver injury.

Acetaminophen (APAP)-induced acute liver injury (AILI) is characterized by extensive cell death and sterile inflammation, with substantial accumulation of myeloid cells in necrotic areas. Macrophages are critical elements in acute hepatic inflammation and resolution. Piezo1 is a mechanically activated ion channel that modulates innate immune responses and senses microenvironmental cues. The functions of myeloid Piezo1 in AILI remain elusive. This study aimed to determine whether myeloid Piezo1 regulates inflammation resolution and macrophage-mediated clearance during AILI. To generate the AILI mouse model, APAP was administered intraperitoneally to Piezo1fl/fl and Piezo1ΔLysM mice, and samples were collected at 6, 24, and 48 h after treatment. Bone marrow-derived macrophages (BMDMs) were stimulated with APAP-treated normal mouse liver cell line (AML12) supernatant to mimic sterile inflammatory response. Liver histology, immunostaining, gene expression analysis, flow cytometry, intracellular Ca2+ measurements, and phagocytosis/efferocytosis assays were performed. Piezo1 exerted protective effects against hepatotoxin-induced liver necrosis and promoted liver recovery after APAP overdose. In vitro assays revealed that Piezo1 alleviated the inflammatory response in bone marrow-derived macrophages. Mechanistically, myeloid Piezo1 manifested a more reparative phenotype and enhanced phagocytic activity by upregulating MerTK expression. Specifically, Piezo1 acted through Ca2+ influx to regulate the expression of MerTK at the target binding stage. Inhibition of MerTK induced more pro-inflammatory mediators and reduced phagocytic ability, phenocopying the Piezo1 deficiency. Separately, Piezo1 modulated cytoskeletal rearrangement via the FAK/Rac1 axis during target internalization. Pharmacological activation of Piezo1 promoted pro-resolution marker expression and enhanced efferocytosis/phagocytic clearance in vitro. This study identified myeloid Piezo1 as an important regulator of macrophage-mediated inflammation resolution and dying-cell clearance during AILI, providing a basis for future exploration of Piezo1-related pathways in macrophage-mediated liver recovery.