αMβ2 Is Antiatherogenic in Female but Not Male Mice

Abstract

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_M^-/-/ApoE^-/- and ApoE^-/- mice were fed a control or high fat diet for 3 or 16 wk to induce atherogenesis. Unexpectedly, α_M 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_M^-/-/ApoE^-/- than in ApoE^-/- mice. Monocyte and macrophage content within the lesions was increased 2.5-fold in female α_M^-/-/ApoE^-/- mice due to enhanced proliferation. α_Mβ₂ elimination promoted gender-dependent foam cell formation due to enhanced uptake of cholesterol by α_M^-/-/ApoE^-/- 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_M^-/-/ApoE^-/- 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_M^-/-/ApoE^-/- 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_M^-/-/ApoE^-/- 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.