Intercellular crosstalk in the pathogenesis of alcohol-associated liver disease (ALD). (IMAGE)

First Hospital of Jilin University

Intercellular crosstalk in the pathogenesis of alcohol-associated liver disease (ALD).

Caption

In response to alcohol, various cellular and molecular changes occur in the liver, contributing to hepatic steatosis, inflammation and fibrosis. Hepatocytes exhibit increased production of reactive oxygen species (ROS) and release damage-associated molecular patterns (DAMPs) along with extracellular vesicles (EVs) containing mitochondrial DNA (mtDNA), microRNA (miRNA) and CD40 ligand (CD40L). This, combined with a reduced NAD+/NADH ratio, promotes the development of hepatic steatosis, inflammation and fibrosis. Macrophages work alongside neutrophils to clear cellular debris; however, continuous alcohol consumption activates macrophages, leading to hepatic inflammation through cytokine secretion and phagocytosis. Kupffer cells (KCs) also contribute to this inflammation by activating hepatic stellate cells (HSCs). A reduced expression of complement receptor of the immunoglobulin superfamily (CRIg) on macrophages has been linked to the progression of ALD. Moreover, interleukin (IL)-1β-containing EVs derived from hepatic macrophages have been implicated in alcohol-induced liver injury and steatosis. Neutrophils contribute to inflammation in ALD through mechanisms such as ROS production, phagocytosis, cytokine release, degranulation and the formation of neutrophil extracellular traps (NETs). Various T cells in the liver, including T helper (Th) 17 cells, regulatory T cells (Tregs), natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells, also play important roles in liver injury in response to alcohol exposure. HSCs respond to alcohol by producing increased amounts of extracellular matrix (ECM) and transforming growth factor-beta (TGF-β), leading to liver fibrosis. Alcohol stimulates HSCs to produce 2-arachidonoylglycerol (2-AG), which binds to cannabinoid receptor 1 (CB1R) on hepatocytes, promoting steatosis. Interestingly, HSCs deficient in neuropilin-1 (NRP-1) have been shown to reduce hepatic steatosis, inflammation and fibrosis in murine models of ALD. Additionally, TGF-β produced by activated HSCs can polarise macrophages towards an M2 phenotype, which exhibits anti-inflammatory functions.

Credit

By Hui Gao, Yanchao Jiang, Ge Zeng, Nazmul Huda, Themis Thoudam, Zhihong Yang, Suthat Liangpunsakul, Jing Ma

Usage Restrictions

Credit must be given to the creator. Only noncommercial uses of the work are permitted.

License

CC BY-NC

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.