Toll-Like Receptors in the Pathogenesis of Alcoholic Liver Disease
Figure 1
Pathophysiology of alcohol-induced liver injury. (a) Ethanol promotes translocation of LPS and other pathogen-associated molecular patterns (PAMPs) from the gut to the portal vein and to the liver. In the liver, LPS induces activation and recruitment of bone marrow-derived inflammatory cells. Activated bone marrow-derived cells synthesize inflammatory cytokines and reactive oxygen species that induce liver injury. Chronic ethanol per se contributes to sensitization of monocytes/macrophages to LPS and to sensitization of hepatocytes to the cytotoxic effect of inflammatory cytokines. The latter is brought about by accumulation of lipids, opening of mitochondrial permeability transition (MPT) pores, and depletion of glutathione (GSH). (b) In macrophages/Kupffer cells, TLR4 recognizes LPS in cooperation with its coreceptors, CD14 and MD-2. The signal is passed through MyD88-dependent or TRIF-dependent intracellular pathways, which activate various transcription factors, including AP-1, NFB, and IRF3, and induces proinflammatory cytokine and Type I interferon genes.
