title: Low TLR7 gene expression in atherosclerotic plaques is associated with major adverse cardio- and cerebrovascular events.
abstract: Processes in the development of atherosclerotic lesions can lead to plaque rupture or erosion, which can in turn elicit myocardial infarction or ischaemic stroke. The aims of this study were to determine whether Toll-like receptor 7 (TLR7) gene expression levels influence patient outcome and to explore the mechanisms linked to TLR7 expression in atherosclerosis.
  
  
  
  Atherosclerotic plaques were removed by carotid endarterectomy (CEA) and subjected to gene array expression analysis (n = 123). Increased levels of TLR7 transcript in the plaques were associated with better outcome in a follow-up study over a maximum of 8 years. Patients with higher TLR7 transcript levels had a lower risk of experiencing major cardiovascular and cerebrovascular events (MACCE) during the follow-up period after CEA (hazard ratio: 2.38, P = 0.012, 95% CI 1.21-4.67). TLR7 was expressed in all plaques by T cells, macrophages and endothelial cells in capillaries, as shown by immunohistochemistry. In short-term tissue cultures, ex vivo treatment of plaques with the TLR7 ligand imiquimod elicited dose-dependent secretion of IL-10, TNF-α, GM-CSF, and IL-12/IL-23p40. This secretion was blocked with a TLR7 inhibitor. Immunofluorescent tissue analysis after TLR7 stimulation showed IL-10 expression in T cells, macrophages and vascular smooth muscle cells. TLR7 mRNA levels in the plaques were correlated with IL-10 receptor (r = 0.4031, P < 0.0001) and GM-CSF receptor A (r = 0.4354, P < 0.0001) transcripts.
  
  
  
  These findings demonstrate that TLR7 is abundantly expressed in human atherosclerotic plaques. TLR7 ligation elicits the secretion of pro-inflammatory and anti-inflammatory cytokines, and high TLR7 expression in plaques is associated with better patient outcome, suggesting that TLR7 is a potential therapeutic target for prevention of complications of atherosclerosis.
authors.affiliation: Unit of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet & Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Glykeria
authors.initials: G
authors.lastname: Karadimou
authors.affiliation: Unit of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet & Karolinska University Hospital, Stockholm, Sweden.|Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Copenhagen, Denmark.
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.affiliation: Unit of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet & Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Berg
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ljubica
authors.initials: L
authors.lastname: Perisic
authors.affiliation: Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Discacciati
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Joy
authors.initials: J
authors.lastname: Roy
authors.affiliation: Unit of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet & Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.affiliation: Unit of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet & Karolinska University Hospital, Stockholm, Sweden.|Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Persson
authors.affiliation: Unit of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet & Karolinska University Hospital, Stockholm, Sweden; gabrielle.berne@ki.se.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Paulsson-Berne
mesh_terms: D000368:Aged; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D016022:Case-Control Studies; D002478:Cells, Cultured; D002561:Cerebrovascular Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016207:Cytokines / Q000378:metabolism; D018572:Disease-Free Survival; D016894:Endarterectomy, Carotid; D005260:Female; D006331:Heart Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058226:Plaque, Atherosclerotic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D051199:Toll-Like Receptor 7 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7
keywords: IL-10; atherosclerosis; carotid stenosis; cytokine; inflammation