title: Proinflammatory Stimulation of Toll-Like Receptor 9 with High Dose CpG ODN 1826 Impairs Endothelial Regeneration and Promotes Atherosclerosis in Mice.
abstract: BACKGROUND
  Toll-like receptors (TLR) of the innate immune system have been closely linked with the development of atherosclerotic lesions. TLR9 is activated by unmethylated CpG motifs within ssDNA, but also by CpG motifs in nucleic acids released during vascular apoptosis and necrosis. The role of TLR9 in vascular disease remains controversial and we sought to investigate the effects of a proinflammatory TLR9 stimulation in mice.
  
  
  RESULTS
  TLR9-stimulation with high dose CpG ODN at concentrations between 6.25 nM to 30 nM induced a significant proinflammatory cytokine response in mice. This was associated with impaired reendothelialization upon acute denudation of the carotid and increased numbers of circulating endothelial microparticles, as a marker for amplified endothelial damage. Chronic TLR9 agonism in apolipoprotein E-deficient (ApoE-/-) mice fed a cholesterol-rich diet increased aortic production of reactive oxygen species, the number of circulating endothelial microparticles, circulating sca-1/flk-1 positive cells, and most importantly augmented atherosclerotic plaque formation when compared to vehicle treated animals. Importantly, high concentrations of CpG ODN are required for these proatherogenic effects.
  
  
  CONCLUSIONS
  Systemic stimulation of TLR9 with high dose CpG ODN impaired reendothelialization upon acute vascular injury and increased atherosclerotic plaque development in ApoE-/- mice. Further studies are necessary to fully decipher the contradictory finding of TLR9 agonism in vascular biology.
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, 53105, Bonn, Germany.
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Krogmann
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, 53105, Bonn, Germany.
authors.forename: Enzo
authors.initials: E
authors.lastname: Lüsebrink
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, 53105, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Steinmetz
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, 53105, Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Asdonk
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, 53105, Bonn, Germany.
authors.forename: Catharina
authors.initials: C
authors.lastname: Lahrmann
authors.affiliation: Institut für klinische Chemie und klinische Pharmakologie, Universität Bonn, 53125, Bonn, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, 53105, Bonn, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, 53105, Bonn, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zimmer
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D001835:Body Weight; D002339:Carotid Arteries / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000235:genetics; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000235:genetics* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012038:Regeneration; D013154:Spleen / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D014652:Vascular Diseases / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C423449:CpG ODN 1826; D016207:Cytokines; D004277:DNA, Single-Stranded; D009838:Oligodeoxyribonucleotides; D017382:Reactive Oxygen Species; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9