Abstract
Background & aims: Acute drug-induced liver injury (DILI) is a major cause of acute liver dysfunction and even liver failure. Peritoneal macrophages have been reported to invade into the injured liver for tissue repair. Herein, we aimed to investigate the role of autophagy-related 16 like 1 gene (ATG16L1) in regulating the reparative function of peritoneal macrophages during DILI caused by acetaminophen (APAP). Methods: Myeloid ATG16L1 knockout (KO), overexpression (KI) or wild-type (WT) mice were challenged with a single dose of intraperitoneal APAP (300 mg/kg) injection. Intraperitoneal injection or depletion of peritoneal macrophages was conducted for the in vivo analysis. Co-culture of primary hepatocytes and peritoneal macrophages were applied for in vitro analysis. Results: Peritoneal macrophages were able to rapidly invade into the liver in response to DILI. Peritoneal macrophage injection promoted, and peritoneal macrophage depletion impaired the resolution of inflammation and liver repair post DILI. DILI triggered ATG16L1 expression in intrahepatic accumulated peritoneal macrophages. Interestingly, compared with WT or KI peritoneal macrophages, KO peritoneal macrophages showed enhanced intrahepatic migration ability via Schlafen family member 5 (SLFN5)-CD44 signaling pathway, leading to less injury at early time of 24 hours post DILI in mice with KO peritoneal macrophage infusion. In addition, ATG16L1-mediated autophagy promoted phagocytosis and reparative phenotype of peritoneal macrophages by regulating reactive oxygen species (ROS)-Mer tyrosine kinase (MerTK) signaling. Moreover, peritoneal macrophage ATG16L1 promoted hepatocyte proliferation dependent on the interleukin (IL)-10-C-X-C motif chemokine receptor 2 (CXCR2) axis. Conclusions: ATG16L1 activation enhanced peritoneal macrophage phagocytosis and reparative phenotype via autophagy-ROS-MerTK signaling and promoted IL-10-CXCR2-dependent hepatocyte proliferation during DILI. Peritoneal macrophage ATG16L1 might be a novel therapeutic target for DILI.