Abstract
Macrophages play pivotal roles in the progression and regression of atherosclerosis. Accumulating evidence suggests that macrophage polarization into an anti-inflammatory M2 state is a key characteristic of atherosclerotic plaques undergoing regression. However, the molecular mechanisms underlying this potential association of the M2 polarization with atherosclerosis regression remain poorly understood. Further, human genetic factors that facilitate these anti-atherogenic processes remain largely unknown. We report that the transcription factor MafB plays pivotal roles in promoting macrophage M2 polarization. Further, MafB promotes cholesterol efflux from macrophage foam cells by directly up-regulating its key cellular mediators. Notably, MafB expression is significantly up-regulated in response to various metabolic and immunological stimuli that promote macrophage M2 polarization or cholesterol efflux, and thereby MafB mediates their beneficial effects, in both liver x receptor (LXR)-dependent and independent manners. In contrast, MafB is strongly down-regulated upon elevated pro-inflammatory signaling or by pro-inflammatory and pro-atherogenic microRNAs, miR-155 and miR-33. Using an integrative systems biology approach, we also revealed that M2 polarization and cholesterol efflux do not necessarily represent inter-dependent events, but MafB is broadly involved in both the processes. These findings highlight physiological protective roles that MafB may play against atherosclerosis progression.
Highlights
Atherosclerosis is characterized by excess accumulation of cholesterol-rich, apolipoprotein B-containing lipoprotein in the subendothelial space of susceptible areas of arteries, which in turn triggers chronic inflammatory responses[1]
We found here that lentivirus-mediated transduction of MafB into mouse bone marrow derived macrophages (BMDM) considerably suppressed induction of a subset of marker genes of classically-activated, pro-inflammatory, M1 macrophages, including nitric oxide synthase 2 (Nos2) and cyclooxygenase 2 (Cox-2), upon treatment of M1-polarizing IFNγ and LPS (Fig. 1a)
Ectopic MafB expression in untreated naïve (M0) BMDM strongly induced marker genes of M2 macrophages, including arginase-1 (Arg-1) and found in inflammatory zone 1 (Fizz-1), which was further potentiated by treatment of a M2 polarizing cytokine IL-4 (Fig. 1b)
Summary
Atherosclerosis is characterized by excess accumulation of cholesterol-rich, apolipoprotein B (apoB)-containing lipoprotein in the subendothelial space (intima) of susceptible areas of arteries, which in turn triggers chronic inflammatory responses[1]. Liver x receptor (LXR) has been shown to play a critical role in RCT by up-regulating expression of several genes that promote cellular cholesterol efflux, including ATP-binding cassette transporters Abca[1] and Abcg[1], and apolipoprotein E (Apoe), which in turn promoted atherosclerotic plaque regression in mouse models[4]. MafB, and to a lesser extent c-Maf, is expressed at an especially high amounts in myeloid cells of the hematopoietic system, and facilitates the establishment and maintenance of the monocyte-macrophage lineage[6] Based on these previously findings, we explored the possibility that MafB may have even broader functional roles in inflammatory responses and M1/M2 polarization of macrophages. These findings highlight physiological protective roles that MafB may play against atherosclerotic plaque progression and therapeutic potentials for targeting MafB to promote atherosclerotic regression
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