COMMD10 Promotes Resolution Of Acetaminophen-Induced Liver Injury By Immunoregulation Of Monocyte And Macrophage Activity

Introduction: Drug-induced liver injury is a challenge for drug development. Hepatocyte necrosis initiates an innate inflammatory response that facilitates the recovery from injury. Using a murine model of acetaminophen-induced liver injury (AILI) we have previously demonstrated that liver resident Kupffer cells (KCs) and infiltrating monocyte-derived macrophages (MoMFs) play an important role in liver resolution. Their local inflammatory response has to be critically regulated to avoid collateral damage and ensure proper liver regeneration, yet, the immunoregulatory mechanisms remain unknown. COMMD family proteins, and specifically COMMD10, are emerging as key regulators of signaling and protein trafficking during inflammation. Here we investigated the cell-specific immunoregulatory circuits orchestrated by COMMD10 in effector Ly6C^hi monocytes, their MoMF descendants and KCs in AILI. Methods: We established a conditional COMMD10-deficient mouse (Commd10^fl/fl). COMMD10-deficiency was targeted to liver Ly6C^hi monocytes, MoMFs and KCs using the Lyz2^cre/+ mice (LysM^ΔCommd10), and specifically to KCs using the Cx3cr1^cre/+ mice (Cx3cr1^ΔCommd10). Results and discussion: LysM^ΔCommd10 and Cx3cr1^ΔCommd10 mice exhibited significantly exacerbated hepatic damage and increased infiltration of pro-inflammatory Ly6C^hi monocytes and neutrophils. Our results outline a pivotal role for COMMD10 in restraining inflammasome activity in Ly6C^hi monocytes. Moreover, COMMD10-deficiency in Ly6C^hi monocytes prominently abolished expression of type I interferon induced genes, which are upregulated upon their differentiation into pro-restorative MoMFs. With respect to resident KCs, COMMD10-deficiency was associated with diminished expression of the apoptotic cell clearance receptors TIM4 and MERTK resulting in their impaired ability to clear damged hepatocytes and neutrophils. Conclusion: COMMD10 plays a pivotal pro-restorative role in AILI via its restraining of inflammasome activity in Ly6C^hi monocytes and promotion of apoptotic cell clearance by KCs.