Inflammation in alcoholic liver disease

Abstract

Frank Burr Mallory's landmark observation in 1911 on the histopathology of alcoholic liver disease (ALD) was the first identification of a link between inflammation and ALD. In this review, we summarize recent advances regarding the origins and roles of various inflammatory components in ALD. Metabolism of ethanol generates a number of metabolites, including acetate, reactive oxygen species, acetaldehyde, and epigenetic changes, that can induce inflammatory responses. Alcohol and its metabolites can also initiate and aggravate inflammatory conditions by promoting gut leakiness of microbial products, by sensitizing immune cells to stimulation, and by activating innate immune pathways, such as complement. Chronic alcohol consumption also sensitizes nonimmune cells, e.g., hepatocytes, to inflammatory signals and impairs their ability to respond to protective signals. Based on these advances, a number of inflammatory targets have been identified with potential for therapeutic intervention in ALD, presenting new opportunities and challenges for translational research.

Fig. 1. Alcohol–induced inflammation in the liver

Emphasis is given to the contribution from hepatocytes and macrophages (Kupffer cells and likely infiltrating monocytes) in inducing proinflammatory mediators required for attracting immune cells (neutrophils, monocytes and lymphocytes) to the liver. Solid lines indicate data with strong evidences and dotted lines indicate data still needs confirmation, including adaptive immune cells. Contributions from stellate cells and endothelial cells to inflammation are not discussed. Terms and items in bright blue indicate immediate inducers for inflammatory response. Abbreviations: ACH, acetaldehyde; AC, acetate; DAMPs, damage associated molecular pattern molecules; HPA, Hypothalamic–pituitary–adrenal; Hif–1α, hypoxia–inducible factor 1 alpha; ROS, reactive oxygen species; C3/C5, complement factors 3a and 5a; SFA, free saturated fatty acid; UFA, unsaturated free fatty acids.