*3.2. NOD-Like Receptors*

The influence of NLRs on liver inflammation and fibrosis was thoroughly reviewed recently by Xu et al. [145]. NOD1, NOD2, and nucleotide-binding oligomerization domain, leucine-rich repeat- and pyrin-domain-containing (NLRP)3 are the main NLRs driving hepatic inflammation, liver injury, and liver fibrogenesis. NOD1-mediated neutrophil recruitment has been described following acute liver injury and inflammation in a CCL4-treated murine model [159]. In addition, activation of NOD-2 by muramyl dipeptide, a bacterial peptidoglycan motif, can induce NF-kB-dependent hepatic expression of pro-inflammatory cytokines to indirectly orchestrate liver inflammation and fibrosis [145,160]. Furthermore, it has been demonstrated that NLRP3–inflammasome pathway is activated in murine NASH to induce hepatic TNF-a, IL-6, and IL-8 production [144,145].

Hepatocyte stimulation of NOD1 via its ligands can activate the NF-kB and MAPK pathway to induce CXCL1 and CCL5 production, promoting wound healing and fibrogenesis [161]. NLRP3–inflammasome has been demonstrated to be a direct contributor in hepatic fibrogenesis. Activation of NLRP3 undoubtedly triggers direct activation of HSC to enhance matrix deposition, TGF-β expression, and fibrosis progression [142].

### *3.3. Anti-Fungal PRRs and Liver Fibrosis*

The role of the CLR dectin-1 in liver inflammation and fibrosis development has been thoroughly studied. Ethanol-containing-diet-fed mice were found to have elevated serum β-glucan level and hepatic injury, which was significantly reduced upon treatment with anti-fungal agent [147]. More importantly, plasma β-glucans enhanced IL-1β expression in KC to drive hepatic inflammation that was absent in dectin-1 deficient mice [147]. A further study showed that hepatic expression of dectin-1 was upregulated in a thioacetamide (TAA)/CCL4 fibrosis mouse model, and that dectin-1 negatively regulated the expression of TLR4 and its co-receptor CD14 to mitigate fibrosis development and hepatic inflammation [146]. Knocking out dectin-1 exacerbated liver fibrosis and inflammation, as demonstrated by increased expression of TNF-α, IL-6, and MCP-1, neutrophil and macrophage influx, and fibrosis progression [146].
