Recent advances of sterile inflammation and inter-organ cross-talk in alcoholic liver disease

Abstract

Alcoholic liver disease (ALD) is one of the fastest-growing concerns worldwide. In addition to bacterial endotoxins in the portal circulation, recent lines of evidence have suggested that sterile inflammation caused by a wide range of stimuli induces alcoholic liver injury, in which damage-associated molecular patterns (DAMPs) play critical roles in inducing de novo lipogenesis and inflammation through the activation of cellular pattern recognition receptors such as Toll-like receptors in non-parenchymal cells. Interestingly, alcohol-mediated metabolic, neurological, and immune stresses stimulate the generation of DAMPs that are released not only in the liver, but also in other organs, such as adipose tissue, intestine, and bone marrow. Thus, diverse DAMPs, including retinoic acids, proteins, lipids, microRNAs, mitochondrial DNA, and mitochondrial double-stranded RNA, contribute to a broad spectrum of ALD through the production of multiple pro-inflammatory cytokines, chemokines, and ligands in non-parenchymal cells, such as Kupffer cells, hepatic stellate cells, and various immune cells. Therefore, this review summarizes recent studies on the identification and understanding of DAMPs, their receptors, and cross-talk between the liver and other organs, and highlights successful therapeutic targets and potential strategies in drug development that can be used to combat ALD. Alcoholic liver disease: cross-talk with other organs Therapies preventing the distribution of damage-associated molecules from other organs to the liver could help tackle alcoholic liver disease (ALD). Over time, metabolites from excessive alcohol consumption induce oxidative stress, damaging liver cells. Injured hepatocytes release molecules known as damage-associated molecular patterns (DAMPs), including proteins, RNA, and metabolites, which disperse within the liver and other organs and trigger chronic inflammation. Won-Il Jeong and Young-Ri Shim at the Korea Advanced Institute of Science and Technology in Daejeon reviewed understanding of DAMPs to identify possible therapeutic targets for ALD. DAMPs are carried between cells by extracellular vesicles, particles released during cellular communication. Alcohol-induced DAMPs in other organs, such as the gut, can deliver to the liver, and it influences ALD progression. The more-detailed cross-talk between the liver and other organs in ALD requires further investigation.