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Reduction of atherosclerosis in mice by inhibition of CD40 signalling

Nature volume 394, pages 200–203 (1998)Cite this article

Abstract

Increasing amounts of evidence support the involvement of inflammation and immunity in atherogenesis1,2,3,4 but mediators of communication between the major cell types in atherosclerotic plaques are poorly defined. Cells in human atherosclerotic lesions express the immune mediator CD40 and its ligand CD40L (also known as CD154 or gp39)5. The interaction of CD40 with CD40L figures prominently in both humoral and cell-mediated immune responses6. CD40L-positive T cells accumulate in atheroma5, and, by virtue of their early appearance, persistence and localization at sites of lesion growth and complication, activated T cells may coordinate important aspects of atherogenesis7,8,9. Interruption of CD40L–CD40 signalling by administration of an anti-CD40L antibody limits experimental autoimmune diseases such as collagen-induced arthritis, lupus nephritis, acute or chronic graft-versus-host disease, multiple sclerosis and thyroiditis10,11,12,13,14. Ligation of CD40 on atheroma-associated cells in vitro activates functions related to atherogenesis, including induction of pro-inflammatory cytokines5, matrix metalloproteinases15,16, adhesion molecules17,18,19 and tissue factor16,20. However, the role of CD40 signalling in atherogenesis in vivo remains unknown. Here we determine whether interruption of CD40 signalling influences atherogenesis in vivo in hyperlipidaemic mice. Treatment with antibody against mouse CD40L limited atherosclerosis in mice lacking the receptor for low-density lipoprotein that had been fed a high-cholesterol diet for 12 weeks. This antibody reduces the size of aortic atherosclerotic lesions by 59% and their lipid content by 79%. Furthermore, atheroma of mice treated with anti-CD40L antibody contained significantly fewer macrophages (64%) and T lymphocytes (70%), and exhibited decreased expression of vascular cell adhesion molecule-1. These data support the involvement of inflammatory pathways in atherosclerosis and indicate a role for CD40 signalling during atherogenesis in hyperlipidaemic mice.

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Figure 1: Expression of CD40 and CD40L in atherosclerotic lesions of LDL-receptor-deficient mice fed a high-cholesterol diet.
Figure 2: Reduction in aortic atherosclerosis by anti-CD40L treatment.
Figure 3: Reduction of atherosclerotic lesion size by anti-CD40L treatment.
Figure 4: Reduction of macrophage and T-lymphocyte content in atheroma by blocking CD40 signalling.
Figure 5: Reduction of VCAM-1 expression by blocking CD40 signalling.
Figure 6: Measurements of aortic-arch-wall area and thickness in LDL-receptor-deficient mice.

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Acknowledgements

We thank E Shvartz, E. Rabkin, and E. Simon-Morrissey for technical assistance; W.C. Fanslow III for providing the rat anti-mouse-CD40L antibody; and M. W. Freeman, K. J. Moore and V. Kunjathoor for assistance and discussions. This work was supported in part by grants from the NHLBI (to P. L.) and from the Fond National Suisse pour la Recherche Scientifique (to F. M.).

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  1. François Mach and Uwe Schönbeck: These authors contributed equally to this work

Authors and Affiliations

  1. Cardiovascular Division, Department of Medicine, Vascular Medicine and Atherosclerosis Unit, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, 02115, Massachusetts, USA

    François Mach, Uwe Schönbeck, Galina K. Sukhova, Elizabeth Atkinson & Peter Libby

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Correspondence to Peter Libby.

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Mach, F., Schönbeck, U., Sukhova, G. et al. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 394, 200–203 (1998). https://doi.org/10.1038/28204

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