| First Author | Szpak D | Year | 2018 |
| Journal | J Immunol | Volume | 200 |
| Issue | 7 | Pages | 2426-2438 |
| PubMed ID | 29459405 | Mgi Jnum | J:262134 |
| Mgi Id | MGI:6152368 | Doi | 10.4049/jimmunol.1700313 |
| Citation | Szpak D, et al. (2018) alphaMbeta2 Is Antiatherogenic in Female but Not Male Mice. J Immunol 200(7):2426-2438 |
| abstractText | Atherosclerosis is a complex inflammatory process characterized by monocyte recruitment into the arterial wall, their differentiation into macrophages, and lipid accumulation. Because integrin alphaMbeta2 (CD11b/CD18) mediates multiple diverse functions of leukocytes, we examined its role in atherogenesis. alphaM(-/-)/ApoE(-/-) and ApoE(-/-) mice were fed a control or high fat diet for 3 or 16 wk to induce atherogenesis. Unexpectedly, alphaM 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 alphaM(-/-)/ApoE(-/-) than in ApoE(-/-) mice. Monocyte and macrophage content within the lesions was increased 2.5-fold in female alphaM(-/-)/ApoE(-/-) mice due to enhanced proliferation. alphaMbeta2 elimination promoted gender-dependent foam cell formation due to enhanced uptake of cholesterol by alphaM(-/-)/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 alphaM(-/-)/ApoE(-/-) mice showed dramatically reduced expression of FoxM1 transcription factor and estrogen receptors (ER) alpha and beta. As their antagonists inhibited the effect of 17beta-estradiol (E2), E2 decreased CD36, SR-A1, and foam cell formation in ApoE(-/-) macrophages in an ERalpha- and ERbeta-dependent manner. However, female alphaM(-/-)/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 alphaM(-/-)/ApoE(-/-) macrophages reversed their proatherogenic phenotype. We demonstrate a new, surprising atheroprotective role of alphaMbeta2 in female ApoE(-/-) mice. alphaMbeta2 maintains ER expression in macrophages and E2-dependent inhibition of foam cell formation. |
