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

Abstract

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. © 2008 by The American Society of Hematology.