title: Toll-like receptors 2 and 4 in ischemic stroke: outcome and therapeutic values.
abstract: Stroke triggers an intense inflammatory response that could be a consequence of Toll-like receptors (TLRs) activation. However, the clinical significance and the therapeutic possibilities of TLR in stroke is not completely clear. In this study, we analyze the association between the expression of TLR2 and TLR4, inflammatory molecules and endogenous ligands, and clinical outcome of ischemic stroke patients, and we test the potential of TLR2/TLR4 and their endogenous ligands as therapeutic targets. For this purpose, we included 110 patients with ischemic stroke finding that TLR2 and TLR4 are independently associated to poor outcome and correlated with higher serum levels of interleukin (IL)1β, IL6, tumor necrosis factor α, and VCAM1, and that TLR4 was independently associated to lesion volume. In addition, we have developed an in vitro model to test the potential therapeutic value of blocking TLR2/TLR4 or their endogenous ligands. Cultured cells (monocytes and human umbilical vein endothelial cells) were treated with serum from ischemic stroke patients, showing a strong inflammatory response that was blocked when TLR2/4 or cellular fibronectin (cFN) or HSP60 were blocked. In conclusion, TLR2 and TLR4 are associated to outcome in stroke patients and TLR2/4 or their endogenous ligands, cFN/HSP60 could be new therapeutic targets for ischemic stroke.
authors.affiliation: Department of Neurology, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Brea
authors.forename: Miguel
authors.initials: M
authors.lastname: Blanco
authors.forename: Pedro
authors.initials: P
authors.lastname: Ramos-Cabrer
authors.forename: Octavio
authors.initials: O
authors.lastname: Moldes
authors.forename: Susana
authors.initials: S
authors.lastname: Arias
authors.forename: María
authors.initials: M
authors.lastname: Pérez-Mato
authors.forename: Rogelio
authors.initials: R
authors.lastname: Leira
authors.forename: Tomás
authors.initials: T
authors.lastname: Sobrino
authors.forename: José
authors.initials: J
authors.lastname: Castillo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000276:immunology; D005260:Female; D005353:Fibronectins / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D020521:Stroke / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D018834:Chaperonin 60; D005353:Fibronectins; D018840:HSP70 Heat-Shock Proteins; D008024:Ligands; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4