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Matrix metalloproteinase 9 is involved in Crohn's disease-associated platelet hyperactivation through the release of soluble CD40 ligand
  1. Luis Menchén (lamenchen.hgugm{at}salud.madrid.org)
  1. Servicio de Aparato Digestivo, Madrid Hospital General Universitario and CIBEREHD, Spain
    1. Ignacio Marín Jiménez (drnachomarin{at}hotmail.com)
    1. Servicio de Aparato Digestivo, Madrid Hospital General Universitario and CIBEREHD, Spain
      1. Elena G Arias-Salgado (egas{at}cib.csic.es)
      1. Centro de Investigaciones Biológicas-CIBERER, Spain
        1. Tomás Fontela (fontela.t{at}cib.csic.es)
        1. Centro de Investigaciones Biológicas-CIBERER, Spain
          1. Paloma Hernández-Sampelayo (phernandez.hgugm{at}salud.madrid.org)
          1. Servicio de Aparato Digestivo, Madrid Hospital General Universitario and CIBEREHD, Spain
            1. María Cruz García Rodríguez (mcruzgarcia.hulp{at}salud.madrid.org)
            1. Immunology Unit, University Hospital “La Paz”, Madrid, Spain
              1. Nora V Butta Coll (nbutta{at}cib.csic.es)
              1. Centro de Investigaciones Biológicas-CIBERER, Spain

                Abstract

                Background: Crohn's disease patients have an increased risk for systemic thromboembolism. Their platelets are hyperactive and possess elevated endogenous content of CD40 ligand, a TNF-α family protein member. Under basal conditions and after stimulation, these platelets express more CD40L in their surface and release higher amounts of soluble (s)CD40L than control ones, through a mechanism that might be mediated by matrix metalloproteinases.

                Objective: The aim of this work is to study whether enhanced sCD40L release secondary to changes in the platelet content of matrix metalloproteinases contributes to the higher state of activation of platelets from Crohn's disease patients.

                Methods: State of activation, CD40L and metalloproteinases content of platelets isolated from patients with Crohn's disease and age- and sex-matched control individuals were analysed, respectively, by flow cytometry, western blot and gelatin zymography.

                Results: Hyperactive state of platelets from Crohn's disease patients might rely on their enhanced sCD40L release, since its inhibition by a broad-range inhibitor of metalloproteinases (GM6001) reduced fibrinogen binding induced by platelets stimulation. Analysis of matrix metalloproteinases content in platelets from Crohn's disease patients showed an exclusive increase in MMP-9 activity. Moreover, MMP-9 inhibition diminished sCD40L release and fibrinogen binding to activated platelets.

                Conclusions: Our results suggest that platelets from Crohn's disease patients release more sCD40L than controls as consequence of their higher endogenous content of CD40L and of MMP-9, which is involved in CD40L shedding. The increased levels of released sCD40L might be responsible, at least in part, for the high state of activation of platelets from Crohn's disease patients.

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