Abstract 15304: Myd88 Signaling in Both DCs and Endothelial Cells Are Required for High-Fat Diet-Induced Atherosclerosis
Background: Studies from our laboratory and others indicate that Innate Immune Receptors TLR2, TLR4, and the adaptor molecule MyD88 promote development of atherosclerosis in hypercholesterolemic mouse. Objective: To investigate the requirement of MyD88 signaling in hematopoietic [i.e. dendritic cells (DCs)], versus stromal cells (i.e. endothelial cells (ECs)] in acceleration of atherosclerosis.
Methods and Results: We created 4 groups of Bone Marrow chimeric mice designated by symbols as Donor → Recipient: 1) ApoE-/-/ MyD88+/+ →ApoE-/-/MyD88-/-; 2) ApoE-/-/MyD88-/- → ApoE-/-; 3) ApoE-/-/MyD88-/- → ApoE-/-/MyD88-/-; and 4) ApoE-/-/ MyD88+/+ → ApoE-/-/ MyD88+/+. Quantification of the lesion area of aortic sinus plaques and lipid content revealed a significant reduction in aortic root lesion size and lipid content in irradiated ApoE-/- mice reconstituted with ApoE-/-/MyD88-/- BM compared to reconstitution with ApoE-/-MyD88+/+ BM despite similar cholesterol. Furthermore. ApoE–/–/MyD88–/– recipient mice reconstituted with ApoE-/-/MyD88+/+ BM also demonstrated a significant reduction in lesion size, and lipid content in aortic sinus, compared with ApoE-/-/MyD88+/+ BM recipients. Lack of MyD88 in either stromal or hematopoietic cells resulted also with a significant decrease in serum IL-12p40 and IL-6. In addition, we generated mice with the specific loss of MyD88 gene only in EC using the cre flox system,Myd88flox/flox Tie2Cre mice and bred these mice onto the ApoE-/- background. The ApoE-/-/Tie2Cre mice had significantly reduced lesion size in aortic sinus and Aorta en face preparations. We crossed the CD11c transgenic MyD88 mice (CD11cTg), (where MyD88 is only expressed in CD11c+ cells, in otherwise MyD88-/- mice) with ApoE-/- mice to specifically investigate the role of MyD88 signaling in CD11c+ DCs. While ApoE-/-;MyD88-/- double KO mice had very little lesion development, the ApoE-/-;Myd88-/-CD11cTg mice had significantly increased lesion in the aortic sinus and aorta.
Conclusion: MyD88 signaling in both hematopoietic cells, especially DCs, as well as stromal cells, such as ECs, play an important role in diet-induced acceleration of atherosclerosis.
- © 2013 by American Heart Association, Inc.