Academic journal article Alcohol Research: Current Reviews

Macrophages and Alcohol-Related Liver Inflammation

Academic journal article Alcohol Research: Current Reviews

Macrophages and Alcohol-Related Liver Inflammation

Article excerpt

Recent studies have suggested that macrophages have a critical role in the development of alcohol-induced inflammation in the liver. To define the precise pathogenic function of these cells during alcoholic liver disease (ALD), it is extremely important to conduct extensive studies in clinical settings that further elucidate the phenotypic diversity of macrophages in the context of ALD. Research to date already has identified several characteristics of macrophages that underlie the cells' actions, including macrophage polarization and their phenotypic diversity. Other analyses have focused on the contributions of resident versus infiltrating macrophages/monocytes, as well as on the roles of macrophage mediators, in the development of ALD. Findings point to the potential of macrophages as a therapeutic target in alcoholic liver injury. Future studies directed toward understanding how alcohol affects macrophage phenotypic switch in the liver and other tissues, whether the liver microenvironment determines macrophage function in ALD, and if targeting of macrophages alleviates alcoholic liver injury, will provide promising strategies to manage patients with alcoholic hepatitis.

Key words: Alcohol consumption; alcoholic liver disease; alcoholic liver injury; alcoholic hepatitis; alcohol-related liver inflammation; liver; immunity; innate immune response; adaptive immune response; macrophage; macrophage phenotypic switch; Kupffer cell


Alcoholic liver disease (ALD) is a complex disease that affects millions of people worldwide and eventually can lead to liver cirrhosis and liver cancer (i.e., hepatocellular carcinoma). Aside from the direct cytotoxic and the oxidative-stress-mediated effects that alcohol and its metabolite, acetaldehyde, exert on hepatocytes, alcohol ingestion activates both the innate and adaptive immune responses in the liver. These responses involve multiple hepatic cell types, including resident macrophages, natural killer cells, natural killer T cells, lymphocytes, and neutrophils. In particular, resident macrophages in the liver, also known as Kupffer cells, are important for clearing pathogens, including bacteria, viruses, immune complexes, bacterial products called endotoxin or lipopolysaccharide (LPS), and tumor cells, from the liver (Jenne and Kubes 2013; Thomson and Knolle 2010). Research tools such as fate mapping, multifocal microscopy, transgenic/reporter mouse models, and next-generation sequencing recently have led to a better understanding of the origins, heterogeneity, and plasticity in the phenotypes and functions of macrophages and rheir circulating precursor cells (i.e., monocytes).

The activation of circulating monocytes and accumulation of macrophages in the liver are important pathophysiological features in patients with ALD. However, the role of hepatic macrophages in the pathogenesis of ALD has not been fully elucidated. This review will discuss some of the new findings in monocyte/macrophage biology, provide an update of the current studies on the involvement of liver macrophages in ALD, and identify remaining questions to be addressed in order to develop macrophage-targeted therapy for ALD.

Phenotypic and Functional Heterogeneity of Monocytes and Macrophages

Macrophages, which play an important role in the initial innate immune response to infection with pathogens or other insults, fall into two main categories--infiltrating macrophages and tissue-resident macrophages. Infiltrating macrophages are derived from precursor cells called monocytes that circulate throughout the body and are recruited into the tissues when an inflammatory reaction occurs. Tissue-resident macrophages, in contrast, always remain localized within one tissue, serving as sentries and first line of defense against any infection or injury in that tissue.

Monocytes are circulating innate immune cells formed from progenitor cells in the bone marrow; the monocytes then differentiate into numerous subsets of macrophages (Fogg et al. …

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