Macrophages are abundant in atherosclerotic plaques and are a pivotal cell type in plaque formation and progression. But how do they get there? Filip Swirski and his colleagues show that, contrary to most previous work that has emphasized the importance of monocyte recruitment from the blood, most macrophages in established lesions are generated by local macrophage proliferation, which depends on the SR-A scavenger receptor. During the inflammatory response that drives atherogenesis, macrophages accumulate progressively in the expanding arterial wall1,2. The observation that circulating monocytes give rise to lesional macrophages3,4,5,6,7,8,9 has reinforced the concept that monocyte infiltration dictates macrophage buildup. Recent work has indicated, however, that macrophage accumulation does not depend on monocyte recruitment in some inflammatory contexts10. We therefore revisited the mechanism underlying macrophage accumulation in atherosclerosis. In murine atherosclerotic lesions, we found that macrophages turn over rapidly, after 4 weeks. Replenishment of macrophages in these experimental atheromata depends predominantly on local macrophage proliferation rather than monocyte influx. The microenvironment orchestrates macrophage proliferation through the involvement of scavenger receptor A (SR-A). Our study reveals macrophage proliferation as a key event in atherosclerosis and identifies macrophage self-renewal as a therapeutic target for cardiovascular disease.

Local proliferation dominates lesional macrophage accumulation in atherosclerosis