title: Toll-like receptor 3 and 4 signalling through the TRIF and TRAM adaptors in haematopoietic cells promotes atherosclerosis.
abstract: OBJECTIVE
  Members of the Toll-like receptor (TLR) family initiate innate immune responses and were recently shown to play a role in atherosclerosis. However, the mechanisms that link TLR ligation to vascular inflammation and atherogenesis remain unclear. To identify which signalling pathways downstream of TLRs in immune cells are pro-atherogenic, we analysed the role of the TLR-specific adaptors MyD88 adaptor-like (MAL), TRIF-related adaptor molecule (TRAM), and TIR-domain-containing adaptor-inducing interferon-β (TRIF) in atherosclerosis.
  
  
  RESULTS
  Using a bone-marrow transplantation strategy into low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice, we could specifically study the absence of the TLR adaptors in immune cells. We showed that haematopoietic deficiency of TRAM and TRIF, but not MAL, reduces atherosclerosis without affecting cholesterol metabolism. This was mediated by decreased aortic inflammation, indicated by lower aortic levels of pro-inflammatory mediators, and reduced influx of macrophages and T cells. Furthermore, by studying Tlr3(-/-) chimeric Ldlr(-/-) mice, we found that deleting TLR3 in immune cells significantly reduced both aortic inflammation and atherosclerotic burden.
  
  
  CONCLUSIONS
  By studying hypercholesterolaemic mice with defects in TLR-signalling adaptors, we demonstrated that deleting either TRAM or TRIF in immune cells is sufficient to attenuate vessel inflammation and protect against atherosclerosis. In addition, these adaptors elicit partly different sets of inflammatory mediators and can independently inhibit the disease process. Furthermore, we identify TLR3 as a pro-atherogenic receptor in haematopoietic immune cells. The identification of these pro-atherogenic pathways downstream of TLR3 and TLR4 contributes to a better understanding of TLRs and their signalling pathways in the pathogenesis of atherosclerosis.
authors: Center for Molecular Medicine, Department of Medicine at Karolinska University Hospital Solna, Karolinska Institutet, Stockholm SE-17176, Sweden.
authors: Anna M
authors: AM
authors: Lundberg
authors: Daniel F J
authors: DF
authors: Ketelhuth
authors: Maria E
authors: ME
authors: Johansson
authors: Norbert
authors: N
authors: Gerdes
authors: Sang
authors: S
authors: Liu
authors: Masahiro
authors: M
authors: Yamamoto
authors: Shizuo
authors: S
authors: Akira
authors: Göran K
authors: GK
authors: Hansson
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D011973:Receptors, LDL; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C499045:TIRAP protein, mouse; C519703:TLR3 protein, mouse; C476416:Ticam2 protein, mouse; C493487:Tlr4 protein, mouse
keywords: Atherosclerosis; TLR3; TRAM; TRIF; Vascular inflammation