title: TLR3 deficiency protects against collagen degradation and medial destruction in murine atherosclerotic plaques.
abstract: OBJECTIVE
  Inflammatory cell activation plays a key role in atherosclerotic plaque growth and acute complications. While secretion of proteases and inflammatory cytokines are likely involved in the development of plaque instability, the precise mechanistic pathways are not well understood.
  
  
  RESULTS
  Based on our previous study, we crossed Toll-like receptor 3 (Tlr3)(-/-) mice with a unique BALB-Apoe(-/-)Npc1(-/-) plaque complication-susceptible mouse model, as well as the widely-used B6-Ldlr(-/-) atherosclerosis model, to test the role of TLR3 signaling in the development of plaque instability. TLR3-deficient mice showed no change in aortic root lesion area, but displayed a marked increase in collagen and smooth muscle cell (SMC) content of lesions. Notably, Apoe(-/-)Npc1(-/-)Tlr3(-/-) mice exhibited a 50% reduction in the incidence of medial destruction, a precursor to aortic aneurysm formation. MMP-2 activity was markedly reduced in aortic extracts from Apoe(-/-)Npc1(-/-)Tlr3(-/-) compared to controls, while both MMP-2 and -9 activities were reduced in Ldlr(-/-)Tlr3(-/-) extracts. Consistent with the in vivo data, TLR3 deficiency suppressed MMP-2 activity induced by TNF-α or polyinosine-polycytidylic acid in macrophages from Apoe(-/-)Npc1(-/-) mice.
  
  
  CONCLUSIONS
  TLR3 plays a critical role in regulating the degradation of extracellular matrix in lesions, in part by modulation of macrophage MMP-2 and -9 activities.
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, P&S 8-401, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Minako
authors.initials: M
authors.lastname: Ishibashi
authors.forename: Scott
authors.initials: S
authors.lastname: Sayers
authors.forename: Jeanine M
authors.initials: JM
authors.lastname: D'Armiento
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Welch
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism; D003094:Collagen / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D058226:Plaque, Atherosclerotic / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D017540:Tunica Media / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D011973:Receptors, LDL; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D003094:Collagen; D002784:Cholesterol; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse