Alcohol and Monocyte Signaling

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 DESCRIPTION (provided by applicant) Macrophages (MØ), Kupffer cells (KC) and neutrophils mediate inflammation 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. 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. We hypothesize that alcohol-induced EVs are important regulators of inflammation and macrophage polarization in the liver. Based on these observations, our aims are: Specific Aim#1: To investigate the role of alcohol-induced extracellular vesicles (EVs) on macrophage activation and polarization by a) evaluating the effects of in vivo alcohol-induced EVs on macrophage polarization in vitro; b) testing the effect of in vivo alcohol-induced EVs on recruitment and phenotype of inflammatory cells in the liver in vivo; c) testing the effect of hepatocyte-derived EVs and their characteristic miRNAs on macrophage polarization in vitro; d) evaluating circulating EVs in human patients with alcoholic hepatitis, characterizing their miRNA composition and effect on monocyte polarization. Specific Aim#2: To investigate triggers of macrophage polarization in ALD by evaluating modulation of neutrophils by alcohol and their role in M1/M2 macrophage polarization in vitro and in vivo in patients with alcoholic hepatitis. Specific Aim#3: To explore the therapeutic potential of interventions that modulate MØ phenotype/polarization on alcohol-induced liver steatosis, inflammation and liver damage in mice.