β2 integrins modulate the initiation and progression of atherosclerosis in low-density lipoprotein receptor knockout mice

beta 2 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 beta 2 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, beta 2 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, beta 2 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. beta 2 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, beta 2 integrins' pro-atherogenic action becomes dominant, accelerating the atherosclerotic process.