title: CD40 is essential in the upregulation of TRAF proteins and NF-kappaB-dependent proinflammatory gene expression after arterial injury.
abstract: Despite extensive investigations, restenosis, which is characterized primarily by neointima formation, remains an unsolved clinical problem after vascular interventions. A recent study has shown that CD40 signaling through TNF receptor associated factor 6 (TRAF6) plays a key role in neointima formation after carotid artery injury; however, underlying mechanisms are not clearly elucidated. Because neointima formation may vary significantly depending on the type of injury, we first assessed the effect of CD40 deficiency on neointima formation in 2 injury models, carotid artery ligation and femoral artery denudation injury. Compared with wild-type mice, CD40 deficiency significantly reduced neointima formation and lumen stenosis in two different models. Further, we investigated the mechanism by which CD40 signaling affects neointima formation after arterial injury. In wild-type mice, the expression levels of CD40, several TRAF proteins, including TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6, as well as total NF-kB p65 and phospho-NF-kB p65, in the carotid artery were markedly upregulated within 3-7 days after carotid ligation. Deficiency of CD40 abolished the injury-induced upregulation of TRAFs including TRAF6 and NF-kB-p65 in the injured vessel wall. Further, CD40(-/-) mice showed a significant decrease in the recruitment of neutrophils (at 3, 7d) and macrophages (at 7, 21d) into injured artery; this effect was most likely attributed to inhibition of NF-kB activation and marked downregulation of NF-kB-related gene expression, including cytokines (TNFα, IL-1β, IL-6), chemokines (MCP-1), and adhesion molecules (ICAM-1, VCAM-1). Moreover, neutrophil recruitment in a model of thioglycollate-induced peritonitis is impaired in CD40-deficient mice. In vitro data revealed that CD40 deficiency blocked CD40L-induced NF-kB p65 nuclear translocation in leukocytes. Altogether, our data identified for the first time that CD40 is essential in the upregulation of TRAF6, NF-kB activation, and NF-kB-dependent proinflammatory genes in vivo. Our findings firmly established the role for CD40 in neointima formation in 2 distinct injury models.
authors.affiliation: Vascular Biology and Stroke Research Laboratory, Department of Neurosurgery, LSU Health Science Center in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Zifang
authors.initials: Z
authors.lastname: Song
authors.forename: Rong
authors.initials: R
authors.lastname: Jin
authors.forename: Shiyong
authors.initials: S
authors.lastname: Yu
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Rivet
authors.forename: Susan S
authors.initials: SS
authors.lastname: Smyth
authors.forename: Anil
authors.initials: A
authors.lastname: Nanda
authors.forename: D Neil
authors.initials: DN
authors.lastname: Granger
authors.forename: Guohong
authors.initials: G
authors.lastname: Li
mesh_terms: D000818:Animals; D001158:Arteries / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D019013:CD40 Antigens / Q000172:deficiency / Q000378:metabolism*; D023201:CD40 Ligand; D020212:Carotid Artery Injuries / Q000150:complications / Q000235:genetics; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000293:injuries / Q000473:pathology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000150:complications / Q000235:genetics* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008026:Ligation; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D058426:Neointima / Q000473:pathology; D020556:Neutrophil Infiltration; D010537:Peritoneum / Q000473:pathology; D013864:Thioglycolates; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D019013:CD40 Antigens; D018836:Inflammation Mediators; D016328:NF-kappa B; D013864:Thioglycolates; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D023201:CD40 Ligand