Reactive Oxygen Species-Mediated TRPM2 Activation Facilitates Phagocytosis of Macrophages to Reverse Profibrotic Phenotype.

BACKGROUND AND AIMS: Macrophages play plastic roles during fibrogenesis and fibrosis regression. Phagocytosis is considered a trigger for shifting macrophages from a profibrotic phenotype to a restorative phenotype. However, the underlying mechanism by which macrophages enhance phagocytosis remains unclear. Our present study investigated the role of reactive oxygen species (ROS)-modulated TRPM2 activation in this process. METHODS: The changes of TRPM2 expression, ROS intensity, and macrophage phagocytosis were assessed in fibrogenesis and fibrosis regression models. RNA sequencing was utilised to reveal pathway enrichment caused by TRPM2, and the role of TRPM2 in enhancing phagocytosis was verified. The coordinate regulation of ROS-TRPM2 in different functions of macrophages was demonstrated by modulating ROS intensity and TRPM2 expression. Mitochondrial dynamics changes induced by ROS-stimulated TRPM2 activation were evaluated by analysing the expression of dynamics-related molecules and mitochondrial imaging, and intervention in mitochondrial dynamics confirmed their impact on macrophage phagocytosis. RESULTS: Low-intensity ROS stimulation up-regulated the expression of TRPM2 and coordinately enhanced macrophage phagocytosis and the expression of matrix degradation-related proteins (MMPs), a process akin to fibrosis regression. However, high-intensity ROS inclined macrophages to produce more profibrotic cytokines, associating with oxidative stress caused by liver injury. ROS-mediated TRPM2 activation mobilised Ca(2+) and promoted mitochondrial fission; either inhibiting mitochondrial fission or chelating Ca(2+) counteracted phagocytosis, as well as decreasing MMPs. CONCLUSIONS: ROS-TRPM2 coordinately regulate macrophage functions. During the liver fibrosis regression period, ROS-induced activation of TRPM2 helps enhance macrophage phagocytosis and switches them to a restorative phenotype. Modulating this process may provide means for developing effective therapeutic strategies.