1. SYK regulates macrophage MHC-II expression via activation of autophagy in response to oxidized LDL
- Author
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Choi, Soo-Ho, Gonen, Ayelet, Diehl, Cody J, Kim, Jungsu, Almazan, Felicidad, Witztum, Joseph L, and Miller, Yury I
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Cardiovascular ,Atherosclerosis ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Animals ,Autophagy ,CD4-Positive T-Lymphocytes ,Epitopes ,Ether-A-Go-Go Potassium Channels ,Histocompatibility Antigens Class II ,Hypercholesterolemia ,Immunoglobulin G ,Intracellular Signaling Peptides and Proteins ,Lipoproteins ,LDL ,Lymphocyte Activation ,Macrophages ,Membrane Glycoproteins ,Mice ,Mice ,Inbred C57BL ,Mitogen-Activated Protein Kinase 8 ,NADPH Oxidase 2 ,NADPH Oxidases ,Oxidation-Reduction ,Protein-Tyrosine Kinases ,Proto-Oncogene Proteins c-bcl-2 ,RAW 264.7 Cells ,Reactive Oxygen Species ,Syk Kinase ,Up-Regulation ,autophagy ,MHC-II ,OxLDL ,oxidation-specific antibodies ,ROS ,SYK ,3MA ,3-methyladenine ,APCs ,antigen-presenting cells ,BCR ,B cell receptor ,BMDM ,bone marrow-derived macrophage ,Baf ,bafilomycin A1 ,DPI ,diphenyleneiodonium ,FCGR ,Fc fragment of IgG ,GFP ,green fluorescent protein ,HFD ,high-fat diet ,IL2 ,interleukin 2 ,ITAM ,immunoreceptor tyrosine-based activation motif ,IgG ,immunoglobulin G ,IgM ,immunoglobulin M ,LPS ,lipopolysaccharide ,MAA-LDL ,malondialdehyde-acetaldehyde modified low density lipoprotein ,MAP1LC3/LC3 ,microtubule-associated protein 1 light chain 3 ,MAPK ,mitogen-activated protein kinase ,MDA-LDL ,malondialdehyde modified low density lipoprotein ,MHC-II ,major histocompatibility complex class II ,NOX ,NAPDH oxidase ,OSE ,oxidation specific epitopes ,OxLDL ,oxidized low density lipoprotein ,PBS ,phosphate-buffered saline ,PIC ,piceatannol ,ROS ,reactive oxygen species ,SYK ,spleen tyrosine kinase ,TCR ,T cell receptor ,TLR4 ,toll-like receptor 4 ,TNF ,tumor necrosis factor ,low affinity ,receptor ,mmLDL ,minimally modified low density lipoprotein ,Biochemistry & Molecular Biology ,Biochemistry and cell biology - Abstract
Adaptive immunity, which plays an important role in the development of atherosclerosis, is mediated by major histocompatibility complex (MHC)-dependent antigen presentation. In atherosclerotic lesions, macrophages constitute an important class of antigen-presenting cells that activate adaptive immune responses to oxidized low-density lipoprotein (OxLDL). It has been reported that autophagy regulates adaptive immune responses by enhancing antigen presentation to MHC class II (MHC-II). In a previous study, we have demonstrated that SYK (spleen tyrosine kinase) regulates generation of reactive oxygen species (ROS) and activation of MAPK8/JNK1 in macrophages. Because ROS and MAPK8 are known to regulate autophagy, in this study we investigated the role of SYK in autophagy, MHC-II expression and adaptive immune response to OxLDL. We demonstrate that OxLDL induces autophagosome formation, MHC-II expression, and phosphorylation of SYK in macrophages. Gene knockout and pharmacological inhibitors of NOX2 and MAPK8 reduced OxLDL-induced autophagy. Using bone marrow-derived macrophages isolated from wild-type and myeloid-specific SYK knockout mice, we demonstrate that SYK regulates OxLDL-induced ROS generation, MAPK8 activation, BECN1-BCL2 dissociation, autophagosome formation and presentation of OxLDL-derived antigens to CD4(+) T cells. ldlr(-/-) syk(-/-) mice fed a high-fat diet produced lower levels of IgG to malondialdehyde (MDA)-LDL, malondialdehyde-acetaldehyde (MAA)-LDL, and OxLDL compared to ldlr(-/-) mice. These results provide new insights into the mechanisms by which SYK regulates MHC-II expression via autophagy in macrophages and may contribute to regulation of adaptive immune responses in atherosclerosis.
- Published
- 2015