α M β 2 Is Antiatherogenic in Female but Not Male Mice

J Immunol. 2018 Apr 1;200(7):2426-2438. doi: 10.4049/jimmunol.1700313. Epub 2018 Feb 19.

Abstract

Atherosclerosis is a complex inflammatory process characterized by monocyte recruitment into the arterial wall, their differentiation into macrophages, and lipid accumulation. Because integrin αMβ2 (CD11b/CD18) mediates multiple diverse functions of leukocytes, we examined its role in atherogenesis. αM-/-/ApoE-/- and ApoE-/- mice were fed a control or high fat diet for 3 or 16 wk to induce atherogenesis. Unexpectedly, αM 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 αM-/-/ApoE-/- than in ApoE-/- mice. Monocyte and macrophage content within the lesions was increased 2.5-fold in female αM-/-/ApoE-/- mice due to enhanced proliferation. αMβ2 elimination promoted gender-dependent foam cell formation due to enhanced uptake of cholesterol by αM-/-/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 αM-/-/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 αM-/-/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 αM-/-/ApoE-/- macrophages reversed their proatherogenic phenotype. We demonstrate a new, surprising atheroprotective role of αMβ2 in female ApoE-/- mice. αMβ2 maintains ER expression in macrophages and E2-dependent inhibition of foam cell formation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / genetics*
  • Atherosclerosis / immunology
  • Atherosclerosis / pathology*
  • CD36 Antigens
  • Cholesterol / metabolism
  • Estradiol / metabolism*
  • Estrogen Receptor alpha / biosynthesis*
  • Estrogen Receptor beta / biosynthesis*
  • Female
  • Foam Cells / cytology
  • Forkhead Box Protein M1 / biosynthesis
  • Macrophage-1 Antigen / immunology*
  • Macrophages / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Scavenger Receptors, Class A / immunology

Substances

  • Apolipoproteins E
  • CD36 Antigens
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Forkhead Box Protein M1
  • Foxm1 protein, mouse
  • Macrophage-1 Antigen
  • Scavenger Receptors, Class A
  • Estradiol
  • Cholesterol