Failed Phenotype Switching by Hepatic Macrophages Produces Persistent Inflammation in Acute Liver Failure

Abstract

Acute liver failure remains a significant health problem with a high rate of mortality. Studies have revealed that acetaminophen‐induced acute liver failure patients with the poorest outcome suffer from a systemic inflammatory response‐like syndrome characterized by excessive production of immunomodulatory cytokines. Unfortunately, the cause of cytokine dysregulation in these patients remains poorly understood. In the present study, we determined whether cytokine dysregulation occurs in mice treated with a dose of acetaminophen that recapitulates many of the features of acute liver failure in patients. Further, we investigated the underlying mechanism. Treatment of mice with a dose of acetaminophen (e.g., 300 mg/kg), normally associated with full liver repair, increased expression of several proinflammatory cytokines, including tumor necrosis factor‐α (TNF‐α). Cytokine levels remained elevated at 48 hours in these mice but returned to baseline by 72 hours. In mice treated with a dose of acetaminophen (e.g., 600 mg/kg) that produces liver injury which fails to repair, cytokine levels were increased out to 48 hours and remained elevated at 72 hours. This indicated a failure to terminate the inflammatory phase of wound healing similar to what occurs in patients. Interestingly, in mice treated with 600 mg/kg acetaminophen, monocyte/macrophages failed to traffic into necrotic lesions and failed to clear dead cell debris by phagocytosis. Studies have suggested that phagocytosis of dead cells terminates cytokine production by proinflammatory monocytes/macrophages. To evaluate this in acetaminophen overdose, proinflammatory monocytes/macrophages were isolated from the livers of mice treated 24 hours earlier with acetaminophen. Exposure of these cells to necrotic hepatocytes increased expression of arginase‐1 and decreased expression of inducible nitric oxide synthase, indicating a switch from an M1‐like proinflammatory macrophage to an M2‐like prorepair macrophage. Further, treatment of these cells with necrotic hepatocytes decreased expression of several proinflammatory cytokines, including TNF‐α. Collectively, these studies suggest that persistent inflammatory cytokine production in some acute liver failure patients may result from a failure of proinflammatory monocytes/macrophages to phagocytose dead cell debris leading to a persistent M1‐like phenotype. Elucidation of the mechanism by which this occurs, could lead to therapies that restore macrophage function and liver repair in acute liver failure patients.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.