title: HMGB1 plays a critical role in vascular inflammation and lesion formation via toll-like receptor 9.
abstract: OBJECTIVE
  Endogenous ligands such as high-mobility group box 1 (HMGB1) and nucleic acids are released by dying cells and bind to Toll-like receptors (TLRs). As TLR9 is involved in both microbial and sterile inflammation by detecting both bacterial and endogenous DNA, we investigated its role in inflammation and lesion formation in a mouse model of vascular injury.
  
  
  RESULTS
  C57BL/6 (WT) and TLR9 KO mice were subjected to wire-mediated vascular injury. Anti-HMGB1 antibody and purified HMGB1 protein were chronically delivered around the injured arteries by gelatin hydrogel, and neointima formation at 4 weeks after injury was evaluated. In addition, the same vascular injury was performed in bone-marrow chimeric mice (WT bone marrow into TLR KO mice; TLR9 KO bone marrow into WT mice). We also evaluated the production of inflammatory cytokines by mouse macrophages in response to HMGB1 and CpG-ODN. In wild-type mice after vascular injury, anti-HMGB1 antibody significantly reduced neointima formation and HMGB1 protein accelerated neointima hyperplasia. HMGB1 failed to accelerate lesion formation in TLR9 KO mice. The bone marrow transplantation study revealed that TLR9 in bone marrow-derived cells played a fundamental role in neointima formation. In vitro, HMGB1 and CpG-ODN synergistically induced the production of inflammatory cytokines by macrophages.
  
  
  CONCLUSIONS
  HMGB1 serves as an endogenous mediator of inflammation and lesion formation via the TLR9 pathway in response to vascular injury. Blockade of HMGB1 and/or TLR9 may represent a novel approach to treating atherosclerosis.
authors.affiliation: Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima-city, Tokushima 770-8503, Japan; Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Kurobe
authors.forename: Mayuko
authors.initials: M
authors.lastname: Higashida
authors.forename: Daiju
authors.initials: D
authors.lastname: Fukuda
authors.forename: Michio
authors.initials: M
authors.lastname: Shimabukuro
authors.forename: Kimie
authors.initials: K
authors.lastname: Tanaka
authors.forename: Yasutomi
authors.initials: Y
authors.lastname: Higashikuni
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kitagawa
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002460:Cell Line; D024243:HMGB1 Protein / Q000378:metabolism / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism*; D008024:Ligands; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058426:Neointima / Q000473:pathology; D009838:Oligodeoxyribonucleotides / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000378:metabolism / Q000502:physiology*
chemical_list: C408982:CPG-oligonucleotide; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D008024:Ligands; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9
keywords: Atherosclerosis; HMGB1; Inflammation; Toll-like receptor; Vascular remodeling