Abstract
Alcoholic liver disease (ALD) is a significant health hazard and economic burden affecting approximately 10 million people in the United States. ALD stems from the production of toxic-reactive metabolites, oxidative stress and fat accumulation in hepatocytes which ultimately results in hepatocyte death promoting hepatitis and fibrosis deposition. Monocyte-derived infiltrating Ly6Chi and Ly6Clow macrophages are instrumental in perpetuating and resolving the hepatitis and fibrosis associated with ALD pathogenesis. In the present study we isolated liver infiltrating macrophages from mice on an ethanol diet and subjected them to metabolomic and proteomic analysis to provide a broad assessment of the cellular metabolite and protein differences between infiltrating macrophage phenotypes. We identified numerous differentially regulated metabolites and proteins between Ly6Chi and Ly6Clow macrophages. Bioinformatic analysis for pathway enrichment of the differentially regulated metabolites showed a significant number of metabolites involved in the processes of glycerophospholipid metabolism, arachidonic acid metabolism and phospholipid biosynthesis. From analysis of the infiltrating macrophage proteome, we observed a significant enrichment in the biological processes of antigen presentation, actin polymerization and organization, phagocytosis and apoptotic regulation. The data presented herein could yield exciting new research avenues for the analysis of signaling pathways regulating macrophage polarization in ALD.
Highlights
Macrophages are instrumental in promoting and resolving the hepatitis and fibrosis associated with Alcoholic liver disease (ALD) as evidenced by clinical observations that macrophage inflammatory genes are upregulated in ALD and cirrhosis patients[8]
From the 102 significantly altered metabolites we observed 6 pathways significantly enriched of which glycerophospholipid metabolism, arachidonic acid metabolism and phospholipid biosynthesis were further analyzed for their potential role in regulating macrophage polarization. (Table 2)
Ly6Chi and Ly6Clow macrophages are significantly enriched for glycerophospholipid metabolism, metabolic pathways, arachidonic acid metabolism, linoleic metabolism and phospholipid biosynthesis with differential regulation of the metabolites involved in each functional pathway (Supplementary Table S1)
Summary
Macrophages are instrumental in promoting and resolving the hepatitis and fibrosis associated with ALD as evidenced by clinical observations that macrophage inflammatory genes are upregulated in ALD and cirrhosis patients[8]. While Ly6Chi macrophages initially exert pro-fibrotic and pro-inflammatory function they can differentiate into Ly6Clow macrophages to facilitate tissue repair and inflammation resolution[20,21]. Macrophages represent an incredibly diverse cell type which, depending on tissue micro-environmental cues, switch from a pro- to anti-inflammatory phenotype in the progression of various diseases. A thorough analysis of the metabolic and protein differences between Ly6Chi and Ly6Clow infiltrating macrophages following ethanol consumption is imperative in understanding the signaling pathways governing macrophage phenotypic switching. This mechanism could be harnessed for targeted therapeutic manipulation of macrophage populations in the liver. The data elucidates novel signaling mechanisms governing macrophage phenotypic switching, with the potential for opening new avenues for therapeutic targeting macrophage polarization in ameliorating ALD progression
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