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Alcohol and Monocyte Signaling

Macrophages (MØ), Kupffer cells (KC) and neutrophils mediate inflammation and play an important role in the pathogenesis of alcoholic liver disease (ALD). Previous studies have demonstrated damaging effects of pro-inflammatory macrophages on alcoholic liver inflammation and high neutrophil infiltration in the liver predicted poor outcome in human alcoholic hepatitis. Prior reports in humans and our preliminary data in mice show that both classically activated inflammatory, M1, and alternatively activated, M2, macrophages are present in the liver after chronic alcohol intake. However, the significance of M1 and M2 type macrophage (MØ) polarization or therapeutic targeting of MØ polarization is yet to be explored in ALD. M2 “alternatively activated” macrophages have anti-inflammatory function and contribute to tissue repair. M2 MØ phenotype is induced and modulated (regulated) by various factors including cytokines, microRNAs, transcription factors or phagocytosis of apoptotic neutrophils. We found decreased phagocytic activity in alcohol exposed MØ and observed decreased apoptosis in neutrophils isolated from livers of chronic alcohol-fed mice. Thus, we hypothesize that insufficient M2 polarization permits chronic inflammation and preferential M1 macrophage phenotype in the liver. We further hypothesize that reduced M2 MØ polarization is due, at least partially, to insufficient phagocytosis of neutrophils. We postulate that therapeutic interventions that promote M2 macrophage polarization will attenuate alcohol-induced liver inflammation and injury. We recently found that MØ polarizing microRNAs are also packaged in extracellular vesicles (EVs), small membrane vesicles that could act as signaling organelles in cell-to-cell communication. In our preliminary experiments, we observed that the number of EVs is increased in the circulation of humans and mice with alcoholic liver injury. Our exciting data shows that when transferred to control mice, EVs from alcohol-fed mice trigger increases in inflammatory MØ cell populations in the liver of recipient mice. We also show that EVs derived from alcohol-exposed hepatocytes have distinct miRNA profile and together with LPS, promote polarization of monocytes into inflammatory macrophages suggesting that EVs have functional effects on target cells. Thus, we hypothesize that alcohol-induced EVs are important regulators of inflammation and macrophage polarization in the liver.