Requirement for CD154 in the progression of atherosclerosis (original) (raw)

Nature Medicine volume 5, pages 1313–1316 (1999)Cite this article

Abstract

Atherosclerosis 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 situ6. 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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Acknowledgements

We thank C. Hughes for the original generation of the CD154 knockout mice. Part of this research was sponsored by the Wynand Pon Foundation, Leusden, the Netherlands. R.A.F. is an investigator and L.G. is an Associate of the Howard Hughes Medical Insitute. I.S.G. was supported by a Juvenile Diabetes Fellowship.

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Author notes

  1. Victor E. Koteliansky and Richard A. Flavell: V.E.K. and R.F. contributed equally to this study.

Authors and Affiliations

  1. Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, P. Debeyeln 25, PO Box 5800, Maastricht, 6202 AZ, The Netherlands
    Esther Lutgens & Mat J.A.P. Daemen
  2. Departments of Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, P. Debeyeln 25, PO Box 5800, Maastricht, 6202 AZ, The Netherlands
    Esther Lutgens & Ebo D. de Muinck
  3. Department of Immunobiology, Howard Hughes Institute, Yale Medical School, 310 Cedar St., New Haven, 06520-8011, Connecticut, USA
    Leonid Gorelik, Iqbal S. Grewal & Richard A. Flavell
  4. Biogen, 14 Cambridge Center, Cambridge, 02142, Massachusetts, USA
    Victor E. Koteliansky

Authors

  1. Esther Lutgens
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  2. Leonid Gorelik
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  3. Mat J.A.P. Daemen
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  4. Ebo D. de Muinck
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  5. Iqbal S. Grewal
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  6. Victor E. Koteliansky
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  7. Richard A. Flavell
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Corresponding author

Correspondence toMat J.A.P. Daemen.

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Lutgens, E., Gorelik, L., Daemen, M. et al. Requirement for CD154 in the progression of atherosclerosis.Nat Med 5, 1313–1316 (1999). https://doi.org/10.1038/15271

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