Origin, Function, and Implications of Intestinal and Hepatic Macrophages in the Pathogenesis of Alcohol-Associated Liver Disease.

Macrophages are members of the human innate immune system, and the majority reside in the liver. In recent years, they have been recognized as essential players in the maintenance of liver and intestinal homeostasis as well as key guardians of their respective immune systems, and they are increasingly being recognized as such. Paradoxically, they are also likely involved in chronic pathologies of the gastrointestinal tract and potentially in the alteration of the gut-liver axis in alcohol use disorder (AUD) and alcohol-associated liver disease (ALD). To date, the causal relationship between macrophages, the pathogenesis of ALD, and the immune dysregulation of the gut remains unclear. In this review, we will discuss our current understanding of the heterogeneity of intestinal and hepatic macrophages, their ontogeny, the potential factors that regulate their origin, and the evidence of how they are associated with the manifestation of chronic inflammation. We will also illustrate how the micro-environment of the intestine shapes the phenotypes and functionality of the macrophage compartment in both the intestines and liver and how they change during chronic alcohol abuse. Finally, we highlight the obstacles to current research and the prospects for this field.