Published online before print May 8, 2006, doi: 10.1161/CIRCULATIONAHA.105.605121
(Circulation. 2006;113:2301-2312.)
© 2006 American Heart Association, Inc.
Molecular Cardiology |
Chemokine CXCL10 Promotes Atherogenesis by Modulating the Local Balance of Effector and Regulatory T Cells
From the Center for Immunology and Inflammatory Diseases (E.A.H., E.L., A.M.T., Q.Y., A.Y.L., N.A., K.J., A.D.L., R.E.G.), Cardiovascular Research Center (E.A.H., E.L., A.Y.L., N.A., R.E.G.), and Center for Molecular Imaging Research (V.M.L., E.A.), Massachusetts General Hospital, Charlestown, Mass, and Harvard Medical School, Boston, Mass; and Lipid Metabolism Unit & Endocrine Division (S.L.K., K.J.M.), Massachusetts General Hospital, Boston, Mass, and Harvard Medical School, Boston, Mass.
Correspondence to Robert E. Gerszten, MD, Cardiology Division and Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital East-8307, 149 13th St, Charlestown, MA 02129. E-mail rgerszten{at}partners.org
Received December 9, 2005; revision received March 6, 2006; accepted March 9, 2006.
Background— Studies to define the overall contribution of lymphocytes to lesion formation in atherosclerosis-susceptible mice have demonstrated relatively subtle effects; the use of lymphocyte-deficient mice, however, compromises both the effector and regulatory arms of the immune system. Here, we tested the hypothesis that deletion of CXCL10 (IP-10), a chemokine specific for effector T cells that has been localized within atherosclerotic lesions, would significantly inhibit atherogenesis.
Methods and Results— Compound deficient Apoe–/–/Cxcl10–/– mice fed a Western-style diet for either 6 or 12 weeks demonstrated significant reductions in atherogenesis as compared with Apoe–/– controls, as assessed by both aortic en face and cross-sectional analyses. Immunohistochemical studies revealed a decrease in the accumulation of CD4+ T cells, whereas quantitative polymerase chain reaction analysis of lesion-rich aortic arches demonstrated a marked reduction in mRNA for CXCR3, the CXCL10 chemokine receptor. Although overall T-cell accumulation was diminished significantly, we found evidence to suggest that regulatory T-cell (Treg) numbers and activity were enhanced, as assessed by increased message for the Treg-specific marker Foxp3, as well as increases in immunostaining for the Treg-associated cytokines interleukin-10 and transforming growth factor-ß1. We also documented naturally occurring Treg cells in human atherosclerotic lesions.
Conclusions— We provide novel evidence for a functional role for the effector T-cell chemoattractant CXCL10 in atherosclerotic lesion formation by modulating the local balance of the effector and regulatory arms of the immune system.
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