title: MicroRNA Cargo of Extracellular Vesicles from Alcohol-exposed Monocytes Signals Naive Monocytes to Differentiate into M2 Macrophages.
abstract: Membrane-coated extracellular vesicles (EVs) released by cells can serve as vehicles for delivery of biological materials and signals. Recently, we demonstrated that alcohol-treated hepatocytes cross-talk with immune cells via exosomes containing microRNA (miRNAs). Here, we hypothesized that alcohol-exposed monocytes can communicate with naive monocytes via EVs. We observed increased numbers of EVs, mostly exosomes, secreted by primary human monocytes and THP-1 monocytic cells in the presence of alcohol in a concentration- and time-dependent manner. EVs derived from alcohol-treated monocytes stimulated naive monocytes to polarize into M2 macrophages as indicated by increased surface expression of CD68 (macrophage marker), M2 markers (CD206 (mannose receptor) and CD163 (scavenger receptor)), secretion of IL-10, and TGFβ and increased phagocytic activity. miRNA profiling of the EVs derived from alcohol-treated THP-1 monocytes revealed high expression of the M2-polarizing miRNA, miR-27a. Treatment of naive monocytes with control EVs overexpressing miR-27a reproduced the effect of EVs from alcohol-treated monocytes on naive monocytes and induced M2 polarization, suggesting that the effect of alcohol EVs was mediated by miR-27a. We found that miR-27a modulated the process of phagocytosis by targeting CD206 expression on monocytes. Importantly, analysis of circulating EVs from plasma of alcoholic hepatitis patients revealed increased numbers of EVs that contained high levels of miR-27a as compared with healthy controls. Our results demonstrate the following: first, alcohol increases EV production in monocytes; second, alcohol-exposed monocytes communicate with naive monocytes via EVs; and third, miR-27a cargo in monocyte-derived EVs can program naive monocytes to polarize into M2 macrophages.
authors.affiliation: From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Banishree
authors.initials: B
authors.lastname: Saha
authors.affiliation: From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Momen-Heravi
authors.affiliation: From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.affiliation: From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 Gyongyi.Szabo@umassmed.edu.
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D016764:Cell Polarity / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology*; D000067128:Extracellular Vesicles / Q000187:drug effects / Q000378:metabolism*; D006519:Hepatitis, Alcoholic / Q000097:blood / Q000235:genetics; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D010641:Phenotype; D034443:RNA Transport / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C508609:IL10 protein, human; D037181:Lectins, C-Type; C531388:MIRN27 microRNA, human; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D035683:MicroRNAs; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D000431:Ethanol
keywords: alcoholic hepatitis; cell signaling; exosome (vesicle); extracellular vesicles; liver injury; phagocytosis