期刊
FRONTIERS IN IMMUNOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.676752
关键词
atherosclerosis; glycogen synthase kinase-3a/beta; macrophage polarization; macrophage function; inflammatory response; bone marrow derived macrophages; Classically activated macrophage; M1 and M2 macrophages
类别
资金
- Canadian Institutes for Health Research (CIHR) [PJT-166092]
- Heart and Stroke Foundation of Canada (HSFC) [G20-0029355]
- HSFC Ontario Mid-Career Investigator Award
The study found that deficiency in GSK3α affects the polarization and inflammatory response of M1 macrophages, while increasing cell migration; deficiency in GSK3β exacerbates the inflammatory response and lipid accumulation of M1 macrophages but decreases cell migration; double deficiency in GSK3α and GSK3β leads to increased cell viability, proliferation, and metabolism.
The molecular and cellular mechanisms that link cardiovascular risk factors to the initiation and progression of atherosclerosis are not understood. Recent findings from our laboratory indicate that endoplasmic reticulum (ER) stress signaling through glycogen synthase kinase (GSK)-3 alpha/beta induces pro-atherosclerotic pathways. The objective of this study was to define the specific roles of GSK3 alpha and GSK3 beta in the activation of pro-atherogenic processes in macrophages. Bone marrow derived macrophages (BMDM) were isolated from low-density lipoprotein receptor knockout (Ldlr(-/-)) mice and Ldlr(-/-) mice with myeloid deficiency of GSK3 alpha and/or GSK3 beta. 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. GSK3 alpha deficiency impairs M1 macrophage polarization, and reduces the inflammatory response and lipid accumulation, but increases macrophage mobility/migration. GSK3 beta deficiency promotes M1 macrophage polarization, which further increases the inflammatory response and lipid accumulation, but decreases macrophage migration. Macrophages deficient in both GSK3 alpha and GSK3 beta exhibit increased cell viability, proliferation, and metabolism. These studies begin to delineate the specific roles of GSK3 alpha and GSK3 beta in macrophage polarization and function. These data suggest that myeloid cell GSK3 alpha signaling regulates M1 macrophage polarization and pro-atherogenic functions to promote atherosclerosis development.
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