The cd40-traf6 axis is the key regulator of the cd40/cd401 system in neointima formation and arterial remodeling

Marjo M.P.C. Donners, Linda Beckers, Dirk Lievens, Imke Munnix, Johan Heemskerk, Ben J. Janssen, Erwin Wijnands, Jack Cleutjens, Alma Zernecke, Christian Weber, Cory L. Ahonen, Ulrike Benbow, Andrew C. Newby, Randolph J. Noelle, Mat J.A.P. Daemen, Esther Lutgens

Research output: Contribution to journalArticlepeer-review


We investigated the role of CD40 and CD40L in neointima formation and identified the downstream CD40-signaling intermediates (tumor necrosis factor [TNF]-receptor associated factors [TRAF]) involved. Neointima formation was induced in wild-type, CD40-/-, CD40L-/-, and in CD40 -/- mice that contained a CD40 transgene with or without mutations at the CD40-TRAF2,3&5, TRAF6, or TRAF2,3,5&6 binding sites. Compared with wild-type mice, CD40-/- mice showed a significant decrease in neointima formation with increased collagen deposition and decreased inflammatory cell infiltration. Neointima formation was also impaired in wild-type mice reconstituted with CD40-/- bone marrow. In vitro, the capacity of CD40-/- leukocytes to adhere to the endothelium was reduced. Ligated carotid arteries of CD40-/- mice showed a smaller total vessel volume and an impaired remodeling capacity, reflected by decreased gelatinolytic/collagenolytic activity. Comparable results were found in mice with defects in CD40-TRAF6 and CD40-TRAF 2/3/5&6 binding, but not in mice with defects in CD40-TRAF2/3&5 binding. Neointima formation and vascular remodeling in CD40-receptor-deficient mice is impaired, dueto a decreased inflammatory cell infiltration and matrix-degrading protease activity, with CD40-TRAF6 signaling as the key regulator. This identifies the CD40-TRAF6 axis as a potential therapeutic target in vascular disease.

Original languageEnglish (US)
Pages (from-to)4596-4604
Number of pages9
Issue number9
StatePublished - May 1 2008

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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