Proposed role of macrophage subsets in formation of the necrotic core. Monocytes are recruited early in atherosclerotic plaque development where, through the action of MCSF (and possibly IL-4, as evident in the mouse model), they differentiate into macrophages (Mϕ), primarily skewed towards an M2 form. Through the uptake of modified lipid they become foam cells. Apoptosis of the foam cells is accompanied by efferocytosis, primarily by M2 macrophages. As the plaque adopts an increasingly inflammatory environment, macrophage differentiation skews towards the M1 form and consequently, M1 foam cells predominate. As M1 macrophages have low efferocytosis capability, and there is a decreasing number of M2 efferocytes, apoptotic foam cells (including any remaining M2: dashed line in figure) undergo secondary necrosis promoting development of the necrotic core.