α_Mβ₂ Is Antiatherogenic in Female but Not Male Mice

Atherosclerosis is a complex inflammatory process characterized by monocyte recruitment into the arterial wall, their differentiation into macrophages, and lipid accumulation. Because integrin α_Mβ₂ (CD11b/CD18) mediates multiple diverse functions of leukocytes, we examined its role in atherogenesis. α and ApoE mice were fed a control or high fat diet for 3 or 16 wk to induce atherogenesis. Unexpectedly, α deficiency accelerated development of atherosclerosis in female but not in male mice. The size of aortic root lesions was 3-4.5-fold larger in female α than in ApoE mice. Monocyte and macrophage content within the lesions was increased 2.5-fold in female α mice due to enhanced proliferation. α_Mβ₂ elimination promoted gender-dependent foam cell formation due to enhanced uptake of cholesterol by α macrophages. This difference was attributed to enhanced expression of lipid uptake receptors, CD36 and scavenger receptor A1 (SR-A1), in female mice. Macrophages from female α mice showed dramatically reduced expression of FoxM1 transcription factor and estrogen receptors (ER) α and β. As their antagonists inhibited the effect of 17β-estradiol (E₂), E₂ decreased CD36, SR-A1, and foam cell formation in ApoE macrophages in an ERα- and ERβ-dependent manner. However, female α macrophages failed to respond to E₂ and maintained elevated CD36, SR-A1, and lipid accumulation. FoxM1 inhibition in ApoE macrophages reduced ERs and enhanced CD36 and SR-A1 expression, whereas FoxM1 overexpression in α macrophages reversed their proatherogenic phenotype. We demonstrate a new, surprising atheroprotective role of α_Mβ₂ in female ApoE mice. α_Mβ₂ maintains ER expression in macrophages and E₂-dependent inhibition of foam cell formation.