**3. Hepatic Recognition of Microbial Ligands: The Role of Pattern Recognition Receptors**

Pattern recognition receptors (PRRs) are a group of host sensors that recognize antigens derived from both foreign and endogenous sources. PRRs are essential initiators of the inflammatory and immune responses that defend against foreign microbial invaders as well as endogenous cellular debris known as damage-associated molecular patterns (DAMPs). While these sensors are an essential component of hepatic immunity, they can contribute to chronic inflammation and fibrosis progression in response to prolonged activation. As outlined in the previous section, the intestinal barrier can become impaired in CLD, allowing continuous translocation of microbial antigens into the portal circulation. This section aimed to characterize the hepatic response to these antigens as it relates to inflammation and fibrosis.

The cellular drivers of liver fibrogenesis are the myofibroblast-like hepatic stellate cells (HSCs). They are largely responsible for wound healing in their steady state, but drive fibrogenesis through ECM deposition upon chronic activation [95]. HSC fibrogenesis can be triggered either directly, via induction of PRRs on HSCs, or indirectly via inflammatory signals produced by neighboring cells such as hepatocytes and Kupffer cells (KCs) [95]. This section covers PRRs that contribute to fibrosis development, with in vivo evidence of inflammatory and fibrogenic activity in CLDs, including toll-like receptor (TLR) 2, TLR3, TLR4, TLR5, TLR7 TLR9, nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), c-type lectin receptors (CLRs), and stimulator of interferon genes (STING). General information regarding PRRs in CLD is summarized in Table 2.


**Table 2.** Pattern recognition receptors (PRRs) that contribute to hepatic inflammation and fibrogenesis.


**Table 2.** *Cont*.

PRR: pattern recognition receptor; TLR: Toll-like receptor; KC: Kupffer cell; HSC: hepatic stellate cell; LPS: lipopolysaccharide; HMGB1: high mobility group box 1 protein; NASH: non-alcoholic steatohepatitis; NAFLD: non-alcoholic fatty liver disease; ALD: alcoholic liver disease; TNF-α: tumor necrosis factor; MCD diet: methionine/choline-deficient diet; LSEC: liver sinusoidal endothelial cell; CDAA: choline-deficient L-amino-defined; CCl4: carbon tetrachloride; α-SMA: α-smooth muscle actin; MAPK: mitogen-activated protein kinase; NF-Kb: nuclear factor kappa-light-chain-enhancer of activated B cells; dsRNA: double-stranded RNA; HFD: highffat diet; DDC: 3,5-diethoxycarbonyl-1,4-dihydrocollidine; NK cell: natural killer cell; COL1A1: collagen type 1 A1; PBMC: peripheral blood mononuclear cell; ROS: reactive oxygen species; HFHC: high-fat, high-cholesterol; KO: knockout; TAK1: transforming growth factor beta-activated kinase 1; ssRNA: single-stranded RNA; IFN: interferon; DC: dendritic cell; NLR: NOD-like receptor; NOD: nucleotide-binding and oligomerization domain; NLRP: nucleotide-binding oligomerization domain, leucine-rich repeat- and pyrin-domain-containing; ATP: adenosine triphosphate; CLR: C-type lectin receptors; STING: Stimulator of Interferon Genes; cGAS: cyclic GMP-AMP Synthase; cGAMP: cyclic GMP-AMP; CDNs: cyclic dinucleotides; IRF3: interferon regulatory transcription factor 3; mtDNA: mitochondrial DNA. ↑: upregulation of expression; ↓: downregulation of expression.
