Alcohol-Induced miR-27a Regulates Differentiation and M2 Macrophage Polarization of Normal Human Monocytes

Abstract

Alcohol abuse is a leading cause of liver disease characterized by liver inflammation, fatty liver, alcoholic hepatitis, or liver cirrhosis. Immunomodulatory effects of alcohol on monocytes and macrophages contribute to alcoholic liver disease. Alcohol use, an independent risk factor for progression of hepatitis C virus (HCV) infection–mediated liver disease, impairs host defense and alters cytokine production and monocyte/macrophage activation. We hypothesized that alcohol and HCV have synergistic effects on the phenotype and function of monocytes. Our data show that acute alcohol binge drinking in healthy volunteers results in increased frequency of CD16+ and CD68+ and M2-type (CD206+, dendritic cell [DC]-SIGN+–expressing and IL-10–secreting) circulating CD14+ monocytes. Expression of HCV-induced CD68 and M2 markers (CD206 and DC-SIGN) in normal monocytes was further enhanced in the presence of alcohol. The levels of microRNA (miR)-27a was significantly upregulated in monocytes cultured in the presence of alcohol or alcohol and HCV as compared with HCV alone. The functional role of miR-27a in macrophage polarization was demonstrated by transfecting monocytes with an miR-27a inhibitor that resulted in reduced alcohol- and HCV- mediated monocyte activation (CD14 and CD68 expression), polarization (CD206 and DC-SIGN expression), and IL-10 secretion. Over-expression of miR-27a in monocytes enhanced IL-10 secretion via activation of the ERK signaling pathway. We found that miR-27a promoted ERK phosphorylation by downregulating the expression of ERK inhibitor sprouty2 in monocytes. Thus, we identified that sprouty2 is a target of miR-27a in human monocytes. In summary, our study demonstrates the regulatory role of miR-27a in alcohol-induced monocyte activation and polarization.

MicroRNA Cargo of Extracellular Vesicles from Alcohol-exposed Monocytes Signals Naive Monocytes to Differentiate into M2 Macrophages

“…that miR-27a was significantly up-regulated in primary monocytes cultured in the presence of alcohol (24). We also demonstrated that alcohol mediates miR-27a induction, which in turn leads to monocyte differentiation and macrophage polarization.…”

“…They are highly plastic, are heterogeneous in their phenotype and function, and are regulated by environmental cues to differentiate into macrophages and polarize. We have recently reported the role of alcohol in modulating monocyte differentiation into an M2-type macrophage phenotype (24). In vivo studies have also shown that patients suffering from alcoholic hepatitis have a presence of both M1 and M2 macrophages (53).…”

“…by Alcohol Treatment-Monocytes become activated in the presence of alcohol and are characterized by changes in the expression of cell surface molecules and the secretion of cytokines and chemokines (24,37,38). Recently, we have reported that alcohol-treated hepatocytes secrete increased numbers of exosomes (16).…”

“…Increasing evidence suggests that miRNAs, a class of non-coding RNAs, play an important role in macrophage polarization (7, 20 -22). We and others have shown that miRNAs can regulate cellular differentiation and functions in immune cells (21,23,24). miRNAs not only function within the cells of origin but can also be packaged into EVs and released into the extracellular environment, where they are transferred in an active form to other cells and exert functional effects (16,(25)(26)(27)(28).…”

MicroRNA Regulation of Atherosclerosis

“…Atherosclerosis progression is associated with the predominance of an M1 macrophage phenotype in the plaque, whereas plaques undergoing regression are enriched in M2 macrophages 92 . A growing list of miRNAs is implicated in regulating the balance between the M1 and M2 phenotypes, including miR-let7a 98 , miR-19a 99 , miR-21 100 , miR-27a 101 , miR-33 42 , miR-124 102 , miR-125a 103 , miR-146a 104 , miR-155 105 , miR-214 106 , miR-223 107 . However, few of these have been investigated in the context of atherosclerosis.…”