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. 2020 Nov;190(11):2185–2193. doi: 10.1016/j.ajpath.2020.08.014

Figure 3.

Figure 3

Overview of lipopolysaccharide (LPS)/CD14/toll-like receptor 4 (TLR4) signaling pathway in alcohol-associated liver disease. Chronic ethanol exposure leads to bacterial translocation and increased leaking of the gut barrier and translocation of LPS from gut to liver. In liver, lipopolysaccharide binding protein (LBP; the shuttle protein) transfers LPS to CD14, which facilitates the binding of LPS to TLR-4/MD-2/IRAK complex. TLR4 undergoes dimerization and transduces signal by MyD88-dependent and TRIF-dependent pathways. The subsequent downstream signaling included the recruitment of IRAK4, IRAK1, and TRAF-6, which ultimately leads to the production of proinflammatory cytokines by the activation of NF-κB, JUNK, Erk1/2, and p38 MAPK pathways. IKK2, inhibitor of nuclear factor kappa-B kinase 2; IRAK, IL-1R–associated kinase; IRF, interferon regulatory factor; JNK1, c-Jun N-terminal kinase 1; MD-2, myeloid differentiation protein-2; TNF-α, tumor necrosis factor-α; TRAF, TNF receptor associated factor; TRIF, TIR-domain-containing adapter-inducing interferon-β.