Defective Leptin/Leptin Receptor Signaling Improves Regulatory T Cell Immune Response and Protects Mice From Atherosclerosis
Taleb, Soraya × Herbin, Olivier Ait-Oufella, Hafid Verreth, Wim Gourdy, Pierre Barateau, Véronique Merval, Régine Esposito, Bruno Clément, Karine Holvoet, Paul Tedgui, Alain Mallat, Ziad #
Lippincott, Williams & Wilkins
Arteriosclerosis, Thrombosis and Vascular Biology vol:27 issue:12 pages:2691-2698
OBJECTIVE: Obesity is a major risk factor for atherosclerosis and is associated with increased cardiovascular morbidity and mortality. However, the precise molecular pathways responsible for this close association remain poorly understood. METHODS AND RESULTS: In this study, we report that leptin-deficiency (ob/ob) in low-density lipoprotein receptor knockout (ldlr(-/-)) mice induces an unexpected 2.2- to 6-fold reduction in atherosclerotic lesion development, compared with ldlr(-/-) mice having similar total cholesterol levels. Ldlr(-/-)/ob/ob mice show reduced T cell helper type 1 (Th1) response, enhanced expression of Foxp3, the specification transcription factor of regulatory T (Treg) cells, and improved Treg cell function. Leptin receptor-deficient (db/db) mice display marked increase in the number and suppressive function of Treg cells. Supplementation of Treg-deficient lymphocytes with Treg cells from db/db mice in an experimental model of atherosclerosis induces a significant reduction of lesion size and a marked inhibition of interferon (INF)-gamma production, compared with supplementation by Treg cells from wild-type mice. CONCLUSIONS: These results identify a critical role for leptin/leptin receptor pathway in the modulation of the regulatory immune response in atherosclerosis, and suggest that alteration in regulatory immunity may predispose obese individuals to atherosclerosis.