Deletion of Myeloid GSK3α Attenuates Atherosclerosis and Promotes an M2 Macrophage Phenotype

Abstract

A therosclerosis is the main underlying pathology of cardiovascular disease, which accounts for the majority of deaths in developed nations.1 Myeloid lineage cells are critical mediators in the development of atherosclerosis and account for the majority of a lesion's cellular bulk.2 Within the atherosclerotic lesion, macrophages phagocytose modified lipid particles becoming lipid engorged foam cells. Foam cells exacerbate disease progression through the secretion of proinflammatory cytokines and growth factors. In advanced lesions, foam cells undergo apoptosis leading to the formation of a lipid-rich, acellular, and highly thrombotic necrotic core. The underlying molecular mechanisms that regulate myeloid cell behavior during atherosclerosis remain poorly defined.Increasing evidence suggests that myeloid cell subpopulations are heterogeneous and have distinctive phenotypes that play unique roles in disease states. Macrophages are often broadly classified as having a classical (M1) or an alternative (M2) phenotype. M1 macrophages, elicited by toll-like receptor or interferon-γ receptor stimulation, are the most prominent macrophages at sites of inflammation and exacerbate the inflammatory response through the secretion of proinflammatory cytokines and chemoatractants.3,4 M1 macrophages promote atherosclerotic lesion development and complexity.5-7 M2 macrophages patrol tissue, perform reparative and immunoregulatory functions, efferocytose debris, and are antiatherogenic. 3,4,8 Other macrophage subtypes have been identified in atherosclerotic lesions, including M4, Mox, and Mhem; however, their roles are less well characterized. 3,5,9,10 Our understanding of the cellular signaling networks that regulate macrophage polarization in the context of atherosclerosis and the relative contribution of each phenotype to the progression and development of atherosclerosis is limited.Glycogen synthase kinase (GSK)-3 α and β are homologous serine/threonine kinases encoded by separate genes. 11GSK3α and GSK3β share 98% amino acid homology within their kinase domain but only 36% homology in the C-terminal domain. GSK3α (51 kDa) is 5 kDa larger than GSK3β (46 kDa) because of an N-terminal glycine-rich domain with an © 2015 American Heart Association, Inc. Objective-Glycogen synthase kinase (GSK)-3α/β has been implicated in the pathogenesis of diabetes mellitus, cancer, Alzheimer, and atherosclerosis. The tissue-and homolog-specific functions of GSK3α and β in atherosclerosis are unknown. This study examines the effect of hepatocyte or myeloid cell deletion of GSK3α or GSK3β on atherosclerosis in low-density lipoprotein receptor (LDLR) −/− mice. Approach and Results-We ablated GSK3α or GSK3β expression in hepatic or myeloid cells of LDLR −/− mice, and mice were fed a high-fat diet for 10 weeks. GSK3α or GSK3β deficiency in hepatic or myeloid cells did not affect metabolic parameters, including plasma lipid levels. Hepatic deletion of GSK3α or GSK3β did not affect the development of atherosclerosis or hepatic lipid content. Myeloid ...

Macrophage-derived foam cells impair endothelial barrier function by inducing endothelial-mesenchymal transition via CCL-4

“…Theoretically speaking, M2 macrophages should be pro-atherogenic due to their pro-angiogenic effects. However, the emerging understanding of macrophage subsets and their functions in atherosclerotic plaque has led to the consensus that M1 macrophages are pro-atherogenic, while M2 macrophages may promote plaque stability (27,28,45), primarily though their tissue repair and anti-inflammatory properties. Additionally, our previous study demonstrated that EndMT damaged endothelial tube formation capacity in an in vitro angiogenesis assay (46), which is consistent with our present results.…”

“…Classically activated M1 macrophages produce tumor necrosis factor (TNF), interleukin (IL)-6 and IL-1β, exacerbating the inflammatory response and promoting the development of atherosclerotic lesions (26). By contrast, alternatively activated M2 macrophages are an anti-inflammatory phenotype and have been reported to be protective in atherosclerosis (27,28). However, despite the central role of macrophages and foam cells in the development of atherosclerosis, their function in the process of EndMT has yet to be determined.…”

Macrophages

“…In this regard, myeloid deletion of GSK3α suppresses STAT1 phosphorylation in response to M1 activation through enhanced STAT3 phosphorylation and formation of STAT3:STAT1 heterodimers, whereas it promotes IL-4-dependent M2 phenotype through enhanced STAT6 phosphorylation. 67 The resulting phenotype is associated with an attenuation of atherosclerosis. 67 Cathepsin C was suggested to alter M1/M2 phenotype in vitro.…”

“…67 The resulting phenotype is associated with an attenuation of atherosclerosis. 67 Cathepsin C was suggested to alter M1/M2 phenotype in vitro. However, the mechanisms were unclear, and no changes of M1/M2 marker expression were detected in vivo in the absence of cathepsin C. 68 Heme uptake and degradation pathways are known to impact macrophage phenotype in vitro and in vivo.…”

Interaction between allergic asthma and atherosclerosis

“…Macrophages within atherosclerotic lesions of myeloid GSK3α-deficient mice, but not of GSK3β-deficient mice, displayed enhanced expression of the M2 markers and reduced expression of markers associated with M1 macrophage polarization; meanwhile GSK3α deletion, but not GSK3β 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 in bone marrow-derived macrophages, suggesting that the deletion of myeloid GSK3α attenuates the progression of atherosclerosis by promoting an M2 macrophage phenotype. 65 Also, to assess the role of Fcγ receptor IIb (FcγR IIb)-signaling in atherosclerosis, apolipoprotein E (ApoE) and FcγRIIb double knockout mice congenic to the C57BL/6 background ( Apoe –/– FcγRIIb B6 –/– ) were generated. These mice had smaller atherosclerotic lesions in the aortic root than those of Apoe –/– control mice.…”