Macrophages (M), 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 (M) polarization or therapeutic targeting of M 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 M 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 M 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 M phenotype/polarization on alcohol-induced liver steatosis, inflammation and liver damage in mice.

Public Health Relevance

Both binge drinking and chronic alcohol use results in abnormal immune system in humans and inflammation in the liver. In this study we will test the role of an immune cell type that is fundamental in inflammation in the liver and in the body. We will track changes in this cell types after alcohol intake in humans and mice and determine whether alcohol-induced changes in the immune response has long-standing organ damage. Our study will also investigate new therapies using specific cell transfers in a mouse model of alcoholic liver disease.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Lin, Li
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University of Massachusetts Medical School Worcester
Internal Medicine/Medicine
Schools of Medicine
United States
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Saha, Banishree; Momen-Heravi, Fatemeh; Furi, Istvan et al. (2018) Extracellular vesicles from mice with alcoholic liver disease carry a distinct protein cargo and induce macrophage activation through heat shock protein 90. Hepatology 67:1986-2000
Bukong, Terence Ndonyi; Cho, Yeonhee; Iracheta-Vellve, Arvin et al. (2018) Abnormal neutrophil traps and impaired efferocytosis contribute to liver injury and sepsis severity after binge alcohol use. J Hepatol 69:1145-1154
Wang, Xiaojing; de Carvalho Ribeiro, Marcelle; Iracheta-Vellve, Arvin et al. (2018) Macrophage-Specific Hypoxia-Inducible Factor-1? Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis. Hepatology :
Bala, Shashi; Csak, Timea; Kodys, Karen et al. (2017) Alcohol-induced miR-155 and HDAC11 inhibit negative regulators of the TLR4 pathway and lead to increased LPS responsiveness of Kupffer cells in alcoholic liver disease. J Leukoc Biol 102:487-498
Saha, Banishree; Momen-Heravi, Fatemeh; Kodys, Karen et al. (2016) MicroRNA Cargo of Extracellular Vesicles from Alcohol-exposed Monocytes Signals Naive Monocytes to Differentiate into M2 Macrophages. J Biol Chem 291:149-59
Ambade, Aditya; Satishchandran, Abhishek; Gyongyosi, Benedek et al. (2016) Adult mouse model of early hepatocellular carcinoma promoted by alcoholic liver disease. World J Gastroenterol 22:4091-108
Ambade, Aditya; Satishchandran, Abhishek; Saha, Banishree et al. (2016) Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1?induced IL-10. Oncoimmunology 5:e1221557
Momen-Heravi, Fatemeh; Bala, Shashi; Kodys, Karen et al. (2015) Exosomes derived from alcohol-treated hepatocytes horizontally transfer liver specific miRNA-122 and sensitize monocytes to LPS. Sci Rep 5:9991
Saha, Banishree; Bruneau, Johanna C; Kodys, Karen et al. (2015) Alcohol-induced miR-27a regulates differentiation and M2 macrophage polarization of normal human monocytes. J Immunol 194:3079-87
Momen-Heravi, Fatemeh; Saha, Banishree; Kodys, Karen et al. (2015) Increased number of circulating exosomes and their microRNA cargos are potential novel biomarkers in alcoholic hepatitis. J Transl Med 13:261

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