β2 integrin-mediated adhesion is thought to be a key event in cardiovascular disease. However, results of clinical trials targeting these molecules have been disappointing. Here, we investigated the effect of inactivation of β2 integrins at different stages of atherosclerosis by timed bone marrow transplantation (BMT) of CD18^−/− cells in low-density lipoprotein receptor knockout (LDLR^−/−) mice.

Early BMT before fatty streak formation revealed a short-term protective effect of CD18 (34% atherosclerotic lesion reduction). Once fatty streak lesions had developed (5-week atherogenic diet) before BMT, β2 integrin expression did not affect lesion progression. However, after the establishment of more mature lesions (pre-feeding mice the atherogenic diet for 10 weeks), CD18^+/+ BMT enhanced atherosclerosis (36%) lesion progression compared with CD18^−/− BMT. Furthermore, β2 integrins modulated the capacity of isolated peritoneal macrophages to take up acetylated LDL and native LDL and to phagocytose apoptotic cells, possibly via CD18-dependent mitogen-activated protein kinase signalling. Gene expression profile of CD18^−/− and CD18^+/+ macrophages revealed significant differences in putative protective as well as atherogenic functions.

β2 integrin-mediated interaction between leucocytes and the vessel wall is a time-dependent and dynamic process. During the initiation phase, it protects against atherosclerotic lesion formation. However, with the evolution of the lesion and chronic exposure to dyslipidaemia, β2 integrins’ pro-atherogenic action becomes dominant, accelerating the atherosclerotic process.