Isoforms GSK3α and GSK3β are 98% homologous in the kinase domain and are expressed ubiquitously ( 15). There are two main forms of GSK3 in mammals: GSK3α (51 kDa) and GSK3β (47 kDa), as well as the splice variant of GSK3β, GSK3β2 ( 14). GSK3 has been linked to several disorders and diseases, including cancer ( 10), bipolar mood disorder ( 11), diabetes ( 12), and Alzheimer’s disease ( 13). Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that plays an important role in many cellular pathways that regulate metabolism and viability. The mechanism(s) and cellular signals that regulate macrophage polarization and other functions that contribute to the development of atherosclerosis are still unclear. Macrophages are directly involved in a variety of processes during atherosclerosis including polarization, foam cell formation, apoptosis, cell viability/proliferation, and migration. The roles and functions of these macrophages are less well understood. Other macrophage subtypes have been identified, including M ox, M hem, and M4 ( 9). M1 macrophages produce pro-inflammatory cytokines (TNFα, IL-1β) and are believed to promote atherosclerotic lesion development and complexity ( 5, 6), whereas M2 macrophages produce anti-inflammatory cytokines (IL-10) and have tissue remodeling properties ( 7, 8). In contrast, M2 anti-inflammatory macrophages can be induced by exposure to T helper type 2 (Th2) cell products, including interleukin (IL)-4 or tumor growth factor (TGF)-β. M1 macrophages can be induced by exposure to T helper type 1 (Th1) cell products, such as interferon (IFN)-γ, or microbial products, such as lipopolysaccharide (LPS) ( 4). The extreme phenotypes are pro-inflammatory (M1) macrophages and anti-inflammatory (M2) macrophages. Macrophages can be polarized into many different subtypes that have distinct characteristics and functions. The underlying molecular mechanisms that regulate macrophage function during the development of atherosclerosis are not completely understood. This can lead to acute cardiovascular complications (myocardial infarction or stroke) and potentially death. Lesion rupture triggers atherothrombosis and can occlude the artery.
Macrophage/foam cell apoptosis leads to the establishment of a necrotic core, which is a key feature of unstable plaques that are prone to rupture. These macrophages take up modified-LDL particles and become foam cells, which form fatty streaks in the artery wall. Monocytes invade the subintima and differentiate into macrophages. Atherosclerosis initiates when endothelial cells (EC) respond to injury, which mediates the attachment and infiltration of monocytes. Macrophages are centrally involved in every stage of the development of atherosclerosis, and they are the main cellular component within the atherosclerotic lesion ( 2, 3). These data suggest that myeloid cell GSK3α signaling regulates M1 macrophage polarization and pro-atherogenic functions to promote atherosclerosis development.Ĭardiovascular disease (CVD) is the leading cause of death in the world today ( 1) and atherosclerosis is a major underlying cause of CVD. These studies begin to delineate the specific roles of GSK3α and GSK3β in macrophage polarization and function. Macrophages deficient in both GSK3α and GSK3β exhibit increased cell viability, proliferation, and metabolism.
GSK3β deficiency promotes M1 macrophage polarization, which further increases the inflammatory response and lipid accumulation, but decreases macrophage migration.
GSK3α deficiency impairs M1 macrophage polarization, and reduces the inflammatory response and lipid accumulation, but increases macrophage mobility/migration.
M1 and M2 macrophages were used to examine functions relevant to the development of atherosclerosis, including polarization, inflammatory response, cell viability, lipid accumulation, migration, and metabolism. Bone marrow derived macrophages (BMDM) were isolated from low-density lipoprotein receptor knockout (Ldlr -/-) mice and Ldlr -/- mice with myeloid deficiency of GSK3α and/or GSK3β. The objective of this study was to define the specific roles of GSK3α and GSK3β in the activation of pro-atherogenic processes in macrophages. Recent findings from our laboratory indicate that endoplasmic reticulum (ER) stress signaling through glycogen synthase kinase (GSK)-3α/β induces pro-atherosclerotic pathways. The molecular and cellular mechanisms that link cardiovascular risk factors to the initiation and progression of atherosclerosis are not understood. 3Department of Medicine, McMaster University, Hamilton, ON, Canada.2Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada.1Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada.Sarvatit Patel 1,2 and Geoff Werstuck 1,2,3*