The atheroprotective effect of 17beta-estradiol depends on complex interactions in adaptive immunity.
Estradiol prevents fatty streak formation in chow-fed atherosclerosis-prone apolipoprotein E (ApoE)-deficient mice. We previously reported that fatty streak development of immunodeficient ApoE(-/-)/recombination activating gene 2 (RAG-2(-/-)) double-deficient mice was insensitive to estradiol. In the present work, we demonstrate that the reconstitution of ApoE(-/-)/RAG-2(-/-) with bone marrow from immunocompetent ApoE(-/-)/RAG-2(+/+) mice restores the protective effect of estradiol on fatty streak constitution. We extended this demonstration to the model of low-density lipoprotein receptor-deficient mice, establishing the obligatory role of mature lymphocytes in this process. We then investigated whether the protective effect of estradiol was mediated by a specific lymphocyte subpopulation by studying the hormonal effect on fatty streak constitution in recently developed models of ApoE(-/-) mice deficient in selective T-lymphocyte subsets (either TCRalphabeta+, CD4+, CD8+, or TCRgammadelta+ lymphocytes) or B lymphocytes. In all these specifically immunodeficient mice, estradiol administration to ovariectomized mice conferred protection as in immunocompetent ApoE(-/-) mice, clearly demonstrating that no single lymphocyte subpopulation was specifically required for this effect. These results point to additional lymphocyte-dependent mechanisms such as modulating the interactions among lymphocytes and between lymphocytes and endothelial and/or antigen-presenting cells.
INSERM U589, IFR31, Institut L. Bugnard, BP 84225, 31432 Toulouse Cédex 4, France.
Rima
R
Elhage
Pierre
P
Gourdy
Jacek
J
Jawien
Laurent
L
Brouchet
Caroine
C
Castano
Catherine
C
Fievet
Göran K
GK
Hansson
Jean-François
JF
Arnal
Francis
F
Bayard
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000276:immunology* / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D010052:Ovariectomy; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D011973:Receptors, LDL; C064655:V(D)J recombination activating protein 2; D004958:Estradiol