LRG1 promotes atherosclerosis by inducing macrophage M1-like polarization

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 35; p. e2405845121
• Main Authors: Wang, Juan, Wang, Jing, Zhong, Jiuchang, Liu, Hongbin, Li, Weiming, Chen, Mulei, Xu, Li, Zhang, Wenbin, Zhang, Ze, Wei, Zhizhong, Guo, Jia, Wang, Xinyu, Sui, Jianhua, Liu, Xingpeng, Zhang, Sitao, Wang, Xiaodong
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27.08.2024
• Subjects: Animals; Apolipoprotein E; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Arteriosclerosis; Atherogenesis; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - immunology; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biomarkers; c-Jun protein; Cardiovascular disease; Cell activation; Cholesterol; Coronary artery disease; Coronary Artery Disease - genetics; Coronary Artery Disease - immunology; Coronary Artery Disease - metabolism; Coronary Artery Disease - pathology; Cytokines - metabolism; Diet, High-Fat - adverse effects; Disease Models, Animal; Extracellular signal-regulated kinase; Female; Glycoproteins; Glycoproteins - genetics; Glycoproteins - metabolism; Heart diseases; High fat diet; Humans; Inflammatory diseases; JNK protein; Kinases; Leucine; Lipoproteins; Macrophage Activation; Macrophages; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Knockout, ApoE; Polarization; Transcription factors; atherosclerosis; macrophage; LRG1; inflammation
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2405845121

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 knockout mice showed significantly delayed atherogenesis progression and reduced levels of macrophage-related proinflammatory cytokines in a high-fat diet-induced 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.