3.1.5. TLR7

The role of TLR7 in NASH/NAFLD, liver fibrosis, or liver cirrhosis has been widely overlooked in the clinical setting; however, recent studies suggest that ALD-mediated inflammation and fibrosis is linked to hepatic TLR7 overexpression [130,131]. Moreover, TLR7-mediated IFN production is stimulated by alcohol in primary human hepatocytes and is correlated with patients with more advanced fibrosis as well as higher expression of fibrotic markers α-SMA, collagen I, and Timp1 [130].

The role of TLR7 in ALD, NASH/NAFLD, and fibrosis development has been established primarily in mouse models. A recent study using ethanol (25% w/v) feeding to stimulate alcoholic hepatitis showed that activation of TLR7 significantly upregulated expression of pro-inflammatory cytokines and the endogenous TLR-7 agonist let-7b from hepatocytes, hence exacerbating hepatic inflammation [131]. Roh et al. recently showed that TLR7 deficiency significantly reduced the degree of hepatic steatosis and inflammation in a MCD-diet-induced NASH mouse model, examined by H&E staining, as well as TNF-α and IFN-α production from KC and hepatic dendritic cells, respectively [132]. In contrast, TLR7 has been identified as a protective factor in hepatic fibrosis development in both CCL4 and BDL murine fibrosis models. TLR7 KO mice expressed higher levels of hepatic pro-inflammatory cytokine and fibrosis marker expression as well as exacerbated collagen deposition [129]. Moreover, dendritic cell expressed type I IFNs upon TLR7 stimulation, triggered KC IL-1 receptor antagonist expression and ultimately suppressing IL-1-dependent liver injury and inflammation [129].
