The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling.
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, due to 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.
Donners
Marjo M P C
MM
Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands.
Beckers
Linda
L
Lievens
Dirk
D
Munnix
Imke
I
Heemskerk
Johan
J
Janssen
Ben J
BJ
Wijnands
Erwin
E
Cleutjens
Jack
J
Zernecke
Alma
A
Weber
Christian
C
Ahonen
Cory L
CL
Benbow
Ulrike
U
Newby
Andrew C
AC
Noelle
Randolph J
RJ
Daemen
Mat J A P
MJ
Lutgens
Esther
E
D000818:Animals; D001158:Arteries / Q000254:growth & development; D001808:Blood Vessels / Q000254:growth & development*; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand / Q000502:physiology*; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D007962:Leukocytes; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology*
D019013:CD40 Antigens; D048029:TNF Receptor-Associated Factor 6; D023201:CD40 Ligand