3.1.1. TLR2

Hepatic upregulation of TLR2 has been observed in patients with NAFLD/NASH [98,100] and fibrosis due to chronic viral infection [152]. In contrast, ALD patients show significantly lower expression of hepatic TLR2 compared to healthy controls [101].

In murine models of CLD, TLR2 significantly contributes to hepatic inflammation and fibrosis. In chronic ethanol-binge-fed mice, TLR2 is crucial for hepatic IL-1β, IL-6, and TNF-α-related liver injury and inflammation, as well as neutrophil-mediated hepatic injury [102,103]. In addition, using the choline-deficient L-amino-defined (CDAA)-diet-induced NASH model, TLR2 deficiency improved hepatic inflammation and injury by reducing Kupffer cell inflammasome activation and pro-inflammatory cytokine production, suggesting a KC-dependent inflammatory pathway mediated by TLR2 [96]. In contrast, TLR2 was protective in the NASH methionine/choline-deficient (MCD) diet model, as demonstrated by an increase in ALT and TNF-α in TLR2 KO mice [104].

In mouse models of fibrosis, TLR2 was reported to have limited contribution to fibrogenesis in bile duct ligation (BDL) mice [105]. In contrast, TLR2−/<sup>−</sup> mice treated with CCL4, possessed significantly impaired HSC activation with reduced collagen deposition, pro-inflammatory cytokine and α-smooth muscle actin (SMA) expression [107]. In addition, they demonstrated attenuated mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation compared to wild type (WT) fibrotic mice. A neutrophil-driven mechanism of fibrogenesis in CCL4-induced fibrosis has also been attributed to TLR2-mediated hepatic chemokine C–C motif ligand (CXCL)2 production [106]. Lastly, TLR2 knockout (KO) in CDAA-diet-induced NASH mice significantly dampened HSC activation, collagen deposition, α-SMA expression, and transforming growth factor (TGF)-β expression, thus, ameliorating NASH-associated fibrogenesis [96].
