Investigation into the role of innate immunity in murine models of acetaminophen-induced liver injury and diet-induced obesity

Abstract

Drug-induced liver injury (DILI) represents a leading cause of adverse drug reactions, as well as the most frequent cause of safety-related drug market withdrawal and prescription restriction. At present, the murine model of acetaminophen (APAP)-induced liver injury (AILI) is the most widely used animal model to study the mechanism of DILI. The pathogenesis of APAP-induced hepatotoxicity consists of both direct cellular damage as well as involvement of the innate immune system. Herein we examine both molecular and cellular mechanisms involved in the progression of tissue injury in AILI. Here we investigate whether following APAP-induced liver injury (AILI) damaged hepatocytes release "danger" signals or damage associated molecular pattern molecules (DAMP), which induce pro-inflammatory activation of hepatic macrophages, further contributing to the progression of liver injury. Our findings reveal that DAMP molecules released from damaged hepatocytes may serve as a crucial link between the initial hepatocyte damage and the activation of innate immune cells following APAP-exposure, and that DAMPs may represent a potential therapeutic target for AILI. Among innate immune cells, hepatic NKT population Natural killer T (NKT) cells represent a predominant population. Although the role of NKT cells in AILI has not been examined directly, earlier studies examining the combined effect of NK and NKT cells in AILI yielded controversial results. Here we show that NKT cell deficient mice developed higher degrees of liver injury than wild-type (WT) mice when treated with APAP. This increased susceptibility in NKT cell-deficient mice was due to their increased expression and activity of CYP2E1 resulting in enhanced APAP metabolism and protein adduct formation. Obesity and its complications represent a major health concern in the United States and worldwide. Nonalcoholic fatty liver disease (NAFLD) is a common liver disorder resulting from obesity. In recent years, growing evidence has suggested that factors thought to control immune responses may also play an integral role in metabolism. Our study revealed a protective role for NKT cells in obesity and metabolic dysfunction. Further insight into the role of NKT in metabolism may assist in the prediction and prevention of AILI, as well as, other types of liver injury.