Integrin-Mediated Leukocyte Recruitment in Atherosclerosis: A Mechanistic Review of β2 Integrins and VLA-4 Signaling Pathways.

Atherosclerosis is a lipid-driven, chronic immunoinflammatory disease in which site-selective leukocyte recruitment converts endothelial dysfunction into sustained arterial-wall inflammation. Among the integrin superfamily, β2 integrins merit focused consideration because they are predominantly expressed on leukocytes and couple chemokine sensing to arrest, adhesion strengthening, crawling, transendothelial migration, phagocytic responses, and outside-in signaling. This mechanistic review examines LFA-1 (αLβ2), Mac-1 (αMβ2), CR4 (αXβ2/CD11c/CD18), and αDβ2 (CD11d/CD18), while positioning VLA-4 (α4β1) as a functionally complementary β1 integrin. We emphasize that leukocyte recruitment is not a rigid receptor-by-receptor sequence: β2 integrins and VLA-4 act cooperatively but are not fully interchangeable, and their contribution varies with leukocyte subset, vascular bed, ligand availability, and inflammatory stage. Disturbed-flow signaling through endothelial fibronectin-binding integrins, particularly α5β1 and αvβ3, provides an upstream mechanotransduction context that increases endothelial adhesiveness and thereby conditions β2/VLA-4-dependent recruitment. Within circulating and lesional myeloid cells, integrin signaling extends beyond adhesion to cytoskeletal organization, phagocytosis, inflammatory gene regulation, lipid-associated phenotypic transitions, and tissue retention. Platelet-leukocyte coupling, especially Mac-1 interaction with platelet GPIbα after selectin-dependent tethering, further links vascular inflammation to thrombosis. Recent single-cell and spatial studies underscore marked plaque-cell heterogeneity, while also cautioning that transcript abundance does not report integrin affinity or avidity state. Clinical translation remains difficult: broad CD18 blockade did not improve outcomes in acute myocardial infarction trials, whereas successful α4-directed therapies in other inflammatory diseases demonstrate druggability but also expose the safety costs of systemic leukocyte-trafficking inhibition. Future strategies should therefore prioritize context-, ligand-, conformation-, and cell-selective modulation rather than indiscriminate integrin suppression.