The role of macrophages in the relationship between senescence and atherosclerosis

Atherosclerosis is a chronic inflammatory disease closely related to senescence, in which the imbalance of macrophage migration plays a key but not yet fully understood role. A clear conceptual distinction must be drawn between two directionally opposite migratory events: the ingress of circulating monocytes into the arterial intima, which is generally pro-atherogenic, and the egress of lipid-laden macrophages out of plaques, which is atheroprotective. Macrophages constitute a heterogeneous population of subpopulations—including M1, M2a–M2d, Mox, M4, Mhem and M(Hb) phenotypes—, each exhibiting distinct migratory capacities and occasionally opposing functions. Consequently, we hypothesize that the migration of macrophages plays a dual, context-dependent role in the pathogenesis of atherosclerosis. Some subsets of macrophages have been observed to promote inflammation and foam cell formation, while others exhibit anti-inflammatory properties and enhance plaque stability. It is crucial to acknowledge that the process of cellular senescence disrupts this balance through multiple pathways. Impaired chemokine receptor expression and intracellular localization, cytoskeletal dysfunction, metabolic reprogramming and defective efferocytosis all weaken directed migration. Concurrently, the senescence-associated secretory phenotype releases proinflammatory factors and induces senescence-associated extracellular vesicles, which continuously maintain a pro-atherosclerotic microenvironment. The regulatory pathways of macrophage migration, including the classic G protein-coupled receptor signaling pathway, guidance cues such as netrin-1, acute-phase proteins, lipoproteins and non-classical mediators, interact with senescence in a polarization-dependent manner. This review integrates recent evidence on the relationship between macrophage migration, senescence and atherosclerosis. We believe that senescence disrupts the balance of macrophage migration, thereby exacerbating atherosclerosis, and that stage- and subset-specific intervention at key targets of macrophage migration may be the key to the precise prevention and control of atherosclerosis.