Deletion of Myeloid GSK3 alpha Attenuates Atherosclerosis and Promotes an M2 Macrophage Phenotype

作者：McAlpine Cameron S; Huang Aric; Emdin Abby; Banko Nicole S; Beriault Daniel R; Shi Yuanyuan; Werstuck Geoff H^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2015, 35(5): 1113-1122.

DOI：10.1161/ATVBAHA.115.305438

• atherosclerosis
• glycogen synthase kinase 3
• myeloid cell

Objective-Glycogen synthase kinase (GSK)-3 alpha/beta has been implicated in the pathogenesis of diabetes mellitus, cancer, Alzheimer, and atherosclerosis. The tissue-and homolog-specific functions of GSK3 alpha and beta in atherosclerosis are unknown. This study examines the effect of hepatocyte or myeloid cell deletion of GSK3 alpha or GSK3 beta on atherosclerosis in low-density lipoprotein receptor (LDLR)(-/-) mice.
Approach and Results-We ablated GSK3 alpha or GSK3 beta expression in hepatic or myeloid cells of LDLR-/- mice, and mice were fed a high-fat diet for 10 weeks. GSK3 alpha or GSK3 beta deficiency in hepatic or myeloid cells did not affect metabolic parameters, including plasma lipid levels. Hepatic deletion of GSK3 alpha or GSK3 beta did not affect the development of atherosclerosis or hepatic lipid content. Myeloid deletion of GSK3 alpha, but not of GSK3 beta, reduced atherosclerotic lesion volume and lesion complexity. Mice lacking GSK3 alpha in myeloid cells had a less inflammatory and more anti-inflammatory plasma cytokine profile. Macrophages within atherosclerotic lesions of myeloid GSK3 alpha-deficient mice, but not of GSK3 beta-deficient mice, displayed reduced expression of markers associated with M1 macrophage polarization and enhanced expression of the M2 markers. Finally, bone marrow-derived macrophages were isolated and differentiated into classical M1 macrophages or alternative M2 macrophages in vitro. GSK3 alpha deletion, but not GSK3 beta deletion, attenuated the expression of genes associated with M1 polarization while promoting the expression of genes associated with M2 polarization by modulating STAT3 and STAT6 activation.
Conclusions-Our findings suggest that deletion of myeloid GSK3 alpha attenuates the progression of atherosclerosis by promoting an M2 macrophage phenotype.

• 出版日期2015-5