TRIF as a Novel Modulator of Liver Inflammation and Fibrosis

he central role of toll-like receptor 4 (TLR4) actiTvation in nonalcoholic steatohepatitis (NASH) has been well-recognized, specifically its role in the activation of innate immune responses, hepatocyte apoptosis, and fibrosis. TLR4 could be activated by various signals; in the context of NASH dysregulation of gut microbial homeostasis, gut leakiness and consequent increase in bacteria-derived lipopolysaccharide (LPS) seem to play a major role. Activation of TLR4 involves adapter proteins including MyD88adaptor-like and TRIF-related adaptor molecule (TRAM) recruiting Myd88 and TRIF, respectively, and ultimately leading to the activation of nuclear factor kappa B and/or interferon-regulatory factor 3 (IRF3). In addition, the sterile aand armadillo-motif-containing protein (SARM) was shown to interact with TRIF, modulating its function. In models of liver injury and fibrosis TRIF has been studied as the main inducer of IRF3. Although earlier reports have demonstrated that stimulator of interferon genes (STING)– mediated IRF3 induction is a key to apoptosis in early alcoholic injury, others concluded that IRF3 is actually protective against steatosis and insulin resistance in nonalcoholic fatty liver disease. To further analyze the reason for these seemingly controversial findings and to delineate the role of the TLR4/TRIF axis in NASH, Yang et al analyzed the cell and pathway-specific roles of TRIF that are responsible for inflammation, steatosis, and fibrosis in NASH. The authors have used TLR4, TLR4/BM chimeric, and TRIF mice on choline-deficient amino acid defined NASH diet for these studies. Although these experiments revealed that intact TLR4/TRIF in both hepatocytes and BM-derived monocytic cells were required for steatosis, surprisingly, TRIF mice exhibited worse inflammation with an increase in alanine aminotransferase, tumor necrosis factor a levels, and hepatocyte ballooning. Consistently, fibrosis was also worse in these mice. Interestingly however, both TLR4 and TRIF hepatocytes were more resistant to palmitate and LPS-induced apoptosis. To identify the possible mechanism for the increased inflammation in TRIF mice, the authors focused on chemokine production and noticed an exacerbated release of CXCL1 and CCL3 in TRIF hepatic stellate cells (HSCs) that were exposed to LPS. On the basis of this, it is plausible that TRIF by a yet unidentified pathway represses the LPS/TLR4/ Myd88 axis in HSCs and controls chemokine production and thereby the recruitment of BM-derived monocytic cells in NASH. The potential direct role of TRIF in hepatocytes also deserves some attention. Notably, TRIF was recently examined in a mouse model of acute sterile inflammation and hepatocyte cell death. In this model TRIF mice had a lower inflammatory response with a reduced recruitment of myeloid cells accompanied by a decrease in CCL2 and