Inflammation in Alcohol-Associated Hepatitis: Pathogenesis and Therapeutic Targets

Abstract

Alcohol-associated hepatitis (AH) is an acute-on-chronic liver injury that occurs in patients with chronic alcohol-associated liver disease (ALD). Patients with severe AH have high short-term mortality and lack effective pharmacologic therapies. Inflammation is believed to be one of the key factors promoting AH progression and has been actively investigated as therapeutic targets over the last several decades, but no effective inflammatory targets have been identified so far. In this review, we discuss how inflammatory cells and the inflammatory mediators produced by these cells contribute to the development and progression of AH, with focus on neutrophils and macrophages. The crosstalk between inflammatory cells and liver nonparenchymal cells in the pathogenesis of AH is elaborated. We also deliberate the application of recent cutting-edge technologies in characterizing liver inflammation in AH. Finally, the potential therapeutic targets of inflammatory mediators for AH are briefly summarized.

Keywords: Alcohol-Associated Hepatitis; Alcohol-Associated Liver Diseases; Inflammation; Single-Cell RNA Sequencing.

Figure 1

Pathogenesis of AH. The schematic depicts key events implicated in the development of AH. Heavy alcohol drinking induces hepatocyte death via numerous mechanisms, including direct alcohol metabolism-related hepatocellular injury, inflammation, and inter-organ crosstalk, including gut-liver and adipose-liver crosstalk.

Figure 2

Crosstalks between immune cells and non-immune cells in the development of AH. Stressed or damaged hepatocytes caused by alcohol intake release cytokines, chemokines, and EVs to recruit and activate macrophages and neutrophils. Activated neutrophils further contribute to hepatocyte injury by producing ROS, NETs, and protease. Neutrophil produced IL-8 attracts infiltration of more neutrophils. Neutrophil-derived ROS also promotes HSC activation, which helps neutrophil recruitment and survival through CXCL1 and GM-CSF. Activated HSCs also facilitate macrophage infiltration and activation through IL-6 and CCL2. After phagocytosis of damaged hepatocytes, macrophages switch from proinflammatory phenotype to a reparative phenotype. Macrophages support HSC activation and proliferation by fibrogentic cytokines (transforming growth factor beta and platelet-derived growth factor B) and proinflammatory cytokines (IL-1 and TNF-α).