Plexin D1 negatively regulates macrophage-derived foam cell migration via the focal adhesion kinase/Paxillin pathway

• Published in: Biochemical and biophysical research communications Vol. 725; p. 150236
• Main Authors: Li, Chenlei, Niu, Yan, Chen, Jie, Geng, Shijia, Wu, Peng, Dai, Lina, Dong, Chongyang, Liu, Rujin, Shi, Yuanjia, Wang, Xiaomeng, Gao, Zhanfeng, Liu, Xiaoyu, Yang, Xi, Gao, Shang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.09.2024
• Subjects: Animals; Atherosclerosis; Atherosclerosis - metabolism; Atherosclerosis - pathology; cdc42 GTP-Binding Protein - metabolism; Cell Movement; Disease Models, Animal; Foam Cells - metabolism; Foam Cells - pathology; Focal adhesion kinase; Focal Adhesion Kinase 1 - genetics; Focal Adhesion Kinase 1 - metabolism; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Intracellular Signaling Peptides and Proteins; Lipoproteins, LDL - metabolism; Macrophages; Macrophages - metabolism; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Migration; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Paxillin; Paxillin - metabolism; Plaque, Atherosclerotic - metabolism; Plaque, Atherosclerotic - pathology; Plexin D1; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Signal Transduction; Focal adhesion kinase; Macrophages; Paxillin; Migration; Atherosclerosis; Plexin D1
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.150236

Macrophage-derived foam cell formation is a hallmark of atherosclerosis and is retained during plaque formation. Strategies to inhibit the accumulation of these cells hold promise as viable options for treating atherosclerosis. Plexin D1 (PLXND1), a member of the Plexin family, has elevated expression in atherosclerotic plaques and correlates with cell migration; however, its role in macrophages remains unclear. We hypothesize that the guidance receptor PLXND1 negatively regulating macrophage mobility to promote the progression of atherosclerosis. We utilized a mouse model of atherosclerosis based on a high-fat diet and an ox-LDL- induced foam cell model to assess PLXND1 levels and their impact on cell migration. Through western blotting, Transwell assays, and immunofluorescence staining, we explored the potential mechanism by which PLXND1 mediates foam cell motility in atherosclerosis. Our study identifies a critical role for PLXND1 in atherosclerosis plaques and in a low-migration capacity foam cell model induced by ox-LDL. In the aortic sinus plaques of ApoE−/− mice, immunofluorescence staining revealed significant upregulation of PLXND1 and Sema3E, with colocalization in macrophages. In macrophages treated with ox-LDL, increased expression of PLXND1 led to reduced pseudopodia formation and decreased migratory capacity. PLXND1 is involved in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK. Additionally, FAK inhibitors counteract the ox-LDL-induced migration suppression by modulating the phosphorylation states of FAK, Paxillin and their downstream effectors CDC42 and PAK. Our findings indicate that PLXND1 plays a role in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK to promoting atherosclerosis. [Display omitted] •Plexin D1 exhibits increased expression in atherosclerosis and foam cell models.•Plexin D1 regulates pseudopodia and migration capacity of macrophage foam cells.•Elevated Plexin D1 inhibits the mobility of foam cells via the FAK/Paxillin pathway.