The Tgfb-Whsc1 Axis Drives Macrophage to Myofibroblast Transition During Wound Repair

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Introduction: Hyperglycemia-induced immunometabolic alterations promote myelopoiesis, increase proinflammatory monocytes, and impair atherosclerosis regression.Identifying critical factors to restore metabolic alterations and promote resolution of inflammation remains an unmet medical need.MicroRNAs (miRs) orchestrate multiple signaling events in macrophages and regulate inflammation.Using miR-seq, we identified miR-369-3p as a novel miR expressed higher in regressing mouse plaques.Therapeutic administration of miR-369-3p promotes plaque regression of diabetes-associated atherosclerosis in mice.The aim of this study was to identify the therapeutic benefits of miR-369-3p overexpression, and the mechanism by which it promotes plaque regression in diabetic mice.Methods: LdlrÀ/À mice were fed HFSC diet for 12 weeks to develop atherosclerotic plaques and were switched to chow diet for 6 weeks to induce regression.During regression, mice received either non-specific control mimic (NS-m) or miR-369-3p mimic (369-m) intravenously twice every week.Immunohistological, morphometric, and flow cytometric analyses were performed to define the changes in plaque, circulation, and bone marrow following 369-m delivery.Results: Therapeutic delivery of 369-m promoted plaque resolution in diabetic mice, evident by reduced plaque area and macrophage content when compared to NS-m injected mice.Circulating proinflammatory cytokines (IL1b, IL6, and TNF-a), total circulating monocytes, and M1 macrophages were decreased in lesions, whereas M2 macrophages were increased in 369-m group.369-m also increased plaque stability and increased FOXP3+ Tregs in plaques when compared to NS-m group.Bioinformatic analyses showed GPR91 and CEBPB as conserved miR targets.Mechanistically, we found that 369-m decreased bone marrow granulocyte-monocyte progenitor population (GMPs), resulting in less inflammatory monocytes, attributed to reduced CEBPB and GPR91 target expression in GMPs.Conclusion: miR-369-3p overexpression reduced plaque-inflammatory macrophages, bone marrow GMPs, and proinflammatory monocytes by regulating macrophage immunometabolism in diabetes-accelerated atherosclerosis in part by targeting CEBPB and GPR91.

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