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CD40L stabilizes arterial thrombi by a β3 integrin–dependent mechanism

Nature Medicine volume 8, pages 247–252 (2002)Cite this article

Abstract

CD40L, a member of the tumor necrosis factor family of ligands, plays a major role in immune responses via its receptor, CD40. Recently, CD40L has been detected on the surfaces of activated platelets and shown to activate endothelium. Here we further addressed the function of platelet CD40L. We show that absence of CD40L affects the stability of arterial thrombi and delays arterial occlusion in vivo. Infusion of recombinant soluble (rs)CD40L restored normal thrombosis, whereas rsCD40L lacking the KGD integrin-recognition sequence did not. CD40-deficient mice exhibited normal thrombogenesis. rsCD40L specifically bound to purified integrin αIIbβ3 and to activated platelets in a β3-dependent manner and induced platelet spreading. In addition, rsCD40L promoted the aggregation of either human or mouse platelets under high shear rates. Thus, CD40L appears to be an αIIbβ3 ligand, a platelet agonist, and necessary for stability of arterial thrombi.

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Figure 1: Quantitative analysis of arterial thrombogenesis in wild-type, CD40−/− and CD40L−/− mice.
Figure 2: Platelet deposition in a collagen-coated perfusion chamber.
Figure 3: Effect of rsCD40L on human thrombi growth at shear rate 1,000/s.
Figure 4: rsCD40L binding to αIIbβ3.
Figure 5: Platelet spreading on rsCD40L-coated glass coverslips.

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Acknowledgements

We thank L. Cowan for help with the preparation of the manuscript. Supported in part by National Heart, Lung and Blood Institute of the National Institutes of Health grants P01 HL56949 and R37 HL41002 (to D.D.W.).

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Authors and Affiliations

  1. The Center for Blood Research, Harvard Medical School, Boston, Massachusetts, USA

    Patrick André, Cécile V. Denis, Jessie M. Papalia & Denisa D. Wagner

  2. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

    Patrick André, Cécile V. Denis & Denisa D. Wagner

  3. COR Therapeutics, South San Francisco, California, USA

    K.S. Srinivasa Prasad, Ming He & David R. Phillips

  4. Howard Hughes Medical Institute, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Masschusetts, USA

    Richard O. Hynes

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Correspondence to Denisa D. Wagner.

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Competing interests

D.P., K.S.S.P. and M.H. are employees of COR Therapeutics. P.A. became an employee of COR Therapeutics after completion of study.

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André, P., Prasad, K., Denis, C. et al. CD40L stabilizes arterial thrombi by a β3 integrin–dependent mechanism. Nat Med 8, 247–252 (2002). https://doi.org/10.1038/nm0302-247

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