SYK regulates macrophage MHC-II expression via activation of autophagy in response to oxidized LDL.

Autophagy ·Vol. 11 ·No. 5 ·2016-02-23

Choi Soo-Ho, Gonen Ayelet, Diehl Cody J, Kim Jungsu, Almazan Felicidad, Witztum Joseph L, Miller Yury I

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.

Keywords

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 MHC-II major histocompatibility complex class II NOX NAPDH oxidase OSE oxidation specific epitopes OxLDL OxLDL oxidized low density lipoprotein PBS phosphate-buffered saline PIC piceatannol ROS ROS reactive oxygen species SYK SYK spleen tyrosine kinase TCR T cell receptor TLR4 toll-like receptor 4 TNF tumor necrosis factor autophagy low affinity receptor mmLDL minimally modified low density lipoprotein oxidation-specific antibodies

Article Info

Journal

Autophagy

Abbr.

Autophagy

ISSN

1554-8627

Published

2016-02-23

Indexed

2015-05-29

Updated

2016-11-25

Language

English

Country/Region

United States

NLM ID

101265188

External Links

PubMed source View journal details

Analysis Services

SYK regulates macrophage MHC-II expression via activation of autophagy in response to oxidized LDL.

Contact

WeChat Official Account