Nature Medicine
5, 1313 - 1316 (1999)
doi:10.1038/15271
Requirement for CD154 in the progression of atherosclerosisEsther Lutgens1, 2, Leonid Gorelik3, Mat J.A.P. Daemen1, Ebo D. de Muinck2, Iqbal S. Grewal3, Victor E. Koteliansky4, 5
& Richard A. Flavell3, 51
Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, P. Debeyeln 25, PO Box 5800, 6202 AZ Maastricht, the Netherlands
2
Departments of Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, P. Debeyeln 25, PO Box 5800, 6202 AZ Maastricht, the Netherlands
3
Department of Immunobiology, Howard Hughes Institute, Yale Medical School, 310 Cedar St., New Haven, Connecticut 06520-8011, USA
4
Biogen, 14 Cambridge Center, Cambridge, Massachusetts, 02142, USA
5
V.E.K. and R.F. contributed equally to this study.
Correspondence should be addressed to Mat J.A.P. Daemen MDA@LPAT.AZM.NLAtherosclerosis is a systemic disease of the large arteries, and activation of inflammatory pathways is important in its pathogenesis1. Increasing evidence supports the importance of CD40−CD154 interactions in atherosclerosis2,
3, interactions originally known to be essential in major immune reactions4 and autoimmune diseases5. CD40 is present on atheroma-derived cells in vitro and in human atheromata in situ
6. Ligation of CD40 on atheroma-associated cells in vitro activates the production of chemokines6, cytokines6, matrix metalloproteinases7,
8, adhesion molecules9,
10 and tissue factor7, substances responsible for lesion progression and plaque destabilization1. Administration of antibody against CD154 to low-density lipoprotein receptor-deficient mice has been shown to reduce atherosclerosis and decrease T-lymphocyte and macrophage content; however, only initial lesions were studied3. Here, we determined the effect of genetic disruption of CD154 in ApoE−/− mice in both initial and advanced atherosclerotic lesions. Plaque area was reduced 550%. In contrast to previous reports, initial lesion development was not affected. Advanced plaques in CD154−/−ApoE−/− mice had a less-lipid-containing, collagen-rich, stable plaque phenotype, with a reduced T-lymphocyte/macrophage content. These data indicate that CD40−CD154 signaling is important in late atherosclerotic changes, such as lipid core formation and plaque destabilization.
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