The Role of CEP250 in Regulating Macrophage Function During Atherosclerosis

Atherosclerosis is a chronic inflammatory disease characterized by lipid accumulation and immune cell infiltration within the arterial wall. Macrophages are the primary immune cells in atherosclerotic plaques, contributing to disease initiation and progression through polarization, infiltration, and lipid uptake, ultimately turning into foam cells, the primary component of atherosclerotic plaques. Despite significant advances, the molecular mechanisms regulating macrophage behavior during atherosclerosis remain poorly understood.Next-generation sequencing of aortas from ApoE-/- mice revealed that centrosomes are involved in the development of atherosclerosis. GWAS further identified a group of single nucleotide polymorphisms (SNPs) in CEP250, the centrosomal core component, associated with a higher risk of atherosclerosis. Analyzing the publicly available singlecell sequencing data revealed that CEP250 levels are higher in macrophages from atherosclerotic plaques. Immunostaining of clinical atherosclerotic specimens and aorta from the mouse model of atherosclerosis further confirmed that the CEP250 level is higher in macrophages from plaques. Preliminary studies further revealed that CEP250 overexpression enhances macrophage polarization, migration, and lipid uptake, suggesting a central role for CEP250 in promoting macrophage-driven plaque formation.GSEA enrichment of transcriptome profile indicated CEP250 overexpression activates the mTOR1 pathway, a critical signaling cascade involved in macrophage polarization, transendothelial migration, and lipid uptake. Further study revealed that CEP250 bound and stabilized the autophagy adaptor protein p62/SQSTM1, a key regulator of aggresomes and aggresome-like induced structures, which play a role in the ubiquitination of misfolded proteins. TurboID2 proximity labeling revealed that CEP250 binding proteins are closely related to RHO GTPase. This phenomenon was confirmed by the GSEA Biocarta enrichment of RNA sequencing data from RAW cells overexpressing CEP250, indicating that the CEP250-p62-RHO GTPase pathway might contribute to the phenotypic changes in macrophages during atherogenesis.This study highlights the central role of CEP250 in regulating macrophage function during atherogenesis, establishing a link between centrosome dynamics, inflammation, migration, phagocytosis, and protein homeostasis. These findings have potential applications in atherosclerosis risk assessment and the development of personalized therapies for cardiovascular disease. Understanding how CEP250 influences macrophage function could lead to novel strategies to modulate macrophage activity and reduce inflammation in atherosclerotic plaques. Furthermore, identifying CEP250 as a biomarker could enhance early diagnosis and risk assessment, providing a tool for personalized treatment. The modulation of macrophage activity by CEP250 may also be relevant in other inflammatory diseases, such as rheumatoid arthritis, cancer, and metabolic disorders, where macrophage-driven inflammation plays a key role.