LRG1 promotes atherosclerosis by inducing macrophage M1-like polarization
Juan Wang, Juan Wang, Jing Wang, Jing Wang, Jiuchang Zhong, Hongbin Liu, Weiming Li, Mulei Chen, Li Xu, Wenbin Zhang, Ze Zhang, Zhizhong Wei, Jia Guo, Xinyu Wang, Xinyu Wang, Jianhua Sui, Xingpeng Liu, Sitao Zhang, Xiaodong Wang, Xiaodong Wang
Abstract
Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by the accumulation of cholesterol-rich lipoproteins in macrophages. How macrophages commit to proinflammatory polarization under atherosclerosis conditions is not clear. Report here that the level of a circulating protein, leucine-rich alpha-2 glycoprotein 1 (LRG1), is elevated in the atherosclerotic tissue and serum samples from patients with coronary artery disease (CAD). LRG1 stimulated macrophages to proinflammatory M1-like polarization through the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways. The LRG1 knockout mice showed significantly delayed atherogenesis progression and reduced levels of macrophage-related proinflammatory cytokines in a high-fat diet–induced Apoe −/− mouse atherosclerosis model. An anti-LRG1 neutralizing antibody also effectively blocked LRG1-induced macrophage M1-like polarization in vitro and conferred therapeutic benefits to animals with ApoE deficiency-induced atherosclerosis. LRG1 may therefore serve as an additional biomarker for CAD and targeting LRG1 could offer a potential therapeutic strategy for CAD patients by mitigating the proinflammatory response of macrophages.