Ambiguous Pathogenic Roles of Macrophages in Alcohol-Associated Liver Diseases

Abstract

Alcohol-associated liver disease (ALD) represents a major public health issue worldwide and is a leading etiology of liver cirrhosis. Alcohol-related liver injuries include a range of manifestations including alcoholic hepatitis (AH), simple steatosis, steatohepatitis, hepatic fibrosis, cirrhosis and liver cancer. Liver disease occurs from several pathological disturbances such as the metabolism of ethanol, which generates reactive oxygen species (ROS) in hepatocytes, alterations in the gut microbiota, and the immune response to these changes. A common hallmark of these liver affections is the establishment of an inflammatory environment, and some (broad) anti-inflammatory approaches are used to treat AH (eg, corticosteroids). Macrophages, which represent the main innate immune cells in the liver, respond to a wide variety of (pathogenic) stimuli and adopt a large spectrum of phenotypes. This translates to a diversity of functions including pathogen and debris clearance, recruitment of other immune cells, activation of fibroblasts, or tissue repair. Thus, macrophage populations play a crucial role in the course of ALD, but the underlying mechanisms driving macrophage polarization and their functionality in ALD are complex. In this review, we explore the various populations of hepatic macrophages in alcohol-associated liver disease and the underlying mechanisms driving their polarization. Additionally, we summarize the crosstalk between hepatic macrophages and other hepatic cell types in ALD, in order to support the exploration of targeted therapeutics by modulating macrophage polarization.

Keywords: alcohol; cirrhosis; fibrosis; liver disease; macrophages.

Figure 1

Hepatic macrophage populations and their roles in ALD. Hepatic macrophages are mainly composed of two ontogenetically distinct subtypes, monocyte-derived macrophages and liver resident Kupffer cells. Each subtype can further be regarded as heterogeneous populations based on their inflammatory properties, functions. Within Kupffer cells (KCs) and monocyte-derived macrophages (MoMFs), pro- and anti-inflammatory subtypes co-exist. The spectrum of macrophage phenotypes and their roles in ALD is presented in a simplified manner in this figure.

Figure 2

Macrophage crosstalk with hepatic cell populations and soluble signals in the context of ALD. Macrophages are sensitive to a wide variety of signals and pathogens and play an essential role in maintaining homeostasis. In the context of ALD, several factors such as extracellular vesicles (EVs) derived from injured hepatocytes, gut derived lipopolysaccharide (LPS) and other mediators can trigger their activation and polarize them towards a pro-inflammatory phenotype. Their interaction and mutual feedback with other non-parenchymal cells such as neutrophils and hepatic stellate cells (HSCs) play a major role in the development or containment of liver injury and fibrosis.