title: TRIF adaptor signaling is important in abdominal aortic aneurysm formation.
abstract: OBJECTIVE
  Abdominal aortic aneurysm (AAA) is characterized by inflammation, loss of smooth muscle cells (SMCs), and degradation of the extracellular matrix in the vessel wall. Innate immune receptors such as Toll-like receptors (TLRs) were recently shown to regulate immunological processes leading to the formation and progression of atherosclerotic plaques as well as to other cardiovascular pathologies. Our aim was to investigate whether blockage of TLR signaling, under the control of TIR domain-containing adaptor protein including IFN-β (TRIF), could inhibit the inflammatory response and AAA development in mice.
  
  
  RESULTS
  In human AAA, an increased TLR3 and TLR4 expression in association with macrophages and T lymphocytes was demonstrated with immunohistochemical analysis. Angiotensin (Ang) II-induced aneurysm formation was significantly reduced by 30% in ApoE(-/-)Trif(-/-) mice compared to ApoE(-/-) mice. Morphologically, AngII-infused ApoE(-/-)Trif(-/-) mice had a more intact cellular and extracellular matrix while ApoE(-/-) mice infused with AngII displayed an increased medial thickness associated with aortic dissection, thrombus formation, and a more disorganized vessel wall. Gene expression analysis of the abdominal aorta revealed a profound decrease of the inflammatory genes CD68 (P < 0.05), CD11b (P < 0.05), and TNF-α (P < 0.05) and the protease gene MMP-12 (P < 0.01) in ApoE(-/-)Trif(-/-) mice compared to ApoE(-/-) mice infused with AngII.
  
  
  CONCLUSIONS
  Our results suggest that signaling through TRIF is important for the inflammatory response of AngII-induced AAA and that blockage of the TRIF pathway reduces vascular inflammation and protects against AAA formation.
authors.affiliation: Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden. Electronic address: emina.vorkapic@liu.se.
authors.forename: Emina
authors.initials: E
authors.lastname: Vorkapic
authors.affiliation: Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institute, Stockholm, Sweden.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Lundberg
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland; HUSLAB, Division of Pathology, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki Finland.
authors.forename: Mikko I
authors.initials: MI
authors.lastname: Mäyränpää
authors.affiliation: Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Dick
authors.initials: D
authors.lastname: Wågsäter
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism*; D001053:Apolipoproteins / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000804:Angiotensin II; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001053:Apolipoproteins; D001057:Apolipoproteins E; D017252:CD3 Complex; D004549:Elastin; D051193:Toll-Like Receptors; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C476286:Ticam1 protein, mouse; C470409:TICAM1 protein, human
keywords: Angiontensin II; Inflammation; Toll-like receptor; Vascular disease