title: Protective role for Toll-like receptor-9 in the development of atherosclerosis in apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9 has a role in the development of atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice.
  
  
  RESULTS
  Newly generated double-knockout ApoE(-/-):TLR9(-/-) mice and control ApoE(-/-) mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE(-/-):TLR9(-/-) mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4(+) T cells. Although ApoE(-/-):TLR9(-/-) mice exhibited an increase in plasma very low-density lipoprotein/low-density-lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE(-/-):TLR9(-/-) mice, CD4(+) T-cell accumulation was further investigated and depletion of these cells in ApoE(-/-):TLR9(-/-) mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9 agonist (type B CpG oligodeoxynucleotide 1668) to ApoE(-/-) mice resulted in a reduction of lesion severity.
  
  
  CONCLUSIONS
  Genetic deletion of the innate immune receptor TLR9 exacerbated atherosclerosis in ApoE(-/-) mice fed a high-fat diet. CD4(+) T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9 agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis.
authors.affiliation: From the Department of Cell Biology & Atherosclerosis (C.K., Y.C.C., C.H., I.A., T.S.K., C.T., A.B., K.P., A.A.) and Department of Diabetic Complications (C.K., T.A., K.J.-D.), Heart and Diabetes Institute, Melbourne, Victoria, Australia; Department of Cardiology and Angiology I, Heart Centre Freiburg University, Freiburg, Germany (I.A.); Molecular Cell Biology Division, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia (M.J.S.); Laboratory of Host Defense, WPI Immunology Frontier Research Centre, Osaka University, Osaka, Japan (S.A.); and Department of Immunology, Monash University, Melbourne, Victoria, Australia (A.B., K.P., A.A.).
authors.forename: Christine
authors.initials: C
authors.lastname: Koulis
authors.forename: Yung-Chih
authors.initials: YC
authors.lastname: Chen
authors.forename: Christian
authors.initials: C
authors.lastname: Hausding
authors.forename: Ingo
authors.initials: I
authors.lastname: Ahrens
authors.forename: Tin Soe
authors.initials: TS
authors.lastname: Kyaw
authors.forename: Christopher
authors.initials: C
authors.lastname: Tay
authors.forename: Terri
authors.initials: T
authors.lastname: Allen
authors.forename: Karin
authors.initials: K
authors.lastname: Jandeleit-Dahm
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Alexander
authors.initials: A
authors.lastname: Bobik
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Peter
authors.forename: Alex
authors.initials: A
authors.lastname: Agrotis
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004041:Dietary Fats / Q000633:toxicity; D018450:Disease Progression; D008075:Lipoproteins, HDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D017737:Macrophages, Peritoneal / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004041:Dietary Fats; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9
keywords: CpG ODN; Toll-like receptor-9; atherosclerosis; inflammation