title: Evidence for a detrimental role of TLR8 in ischemic stroke.
abstract: Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors that initiate signals in response to diverse pathogen-associated molecular patterns. Several groups have recently reported a role for TLR2 and TLR4 in ischemic stroke-induced brain injury. However, relatively little is known about the role of TLR8 in ischemic stroke. Here we provide the first evidence that TLR8 activation plays a detrimental role in stroke outcome by promoting neuronal apoptosis and T cell-mediated post-stroke inflammation. TLR8 is expressed in cerebral cortical neurons, where its levels and downstream signaling via JNK are increased in response to oxygen glucose deprivation (OGD). Treatment with a TLR8 agonist activated pro-apoptotic JNK and increased neuronal cell death during OGD. Furthermore, selective knockdown of TLR8 using siRNA protected SH-SY5Y cells following OGD, and TLR8 agonist administration in vivo increased mortality, neurological deficit and T cell infiltration following stroke. Taken together, our findings indicate a detrimental role for neuronal TLR8 signaling in the triggering of post-stroke inflammation and neuronal death.
authors.affiliation: Stroke Center, Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Sung-Chun
authors.initials: SC
authors.lastname: Tang
authors.forename: Shin-Joe
authors.initials: SJ
authors.lastname: Yeh
authors.forename: Yu-I
authors.initials: YI
authors.lastname: Li
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Wang
authors.forename: Sang-Ha
authors.initials: SH
authors.lastname: Baik
authors.forename: Tomislav
authors.initials: T
authors.lastname: Santro
authors.forename: Alexander
authors.initials: A
authors.lastname: Widiapradja
authors.forename: Silvia
authors.initials: S
authors.lastname: Manzanero
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.forename: Jiann-Shing
authors.initials: JS
authors.lastname: Jeng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002460:Cell Line; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D020521:Stroke / Q000276:immunology / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000276:immunology / Q000378:metabolism*
chemical_list: C552579:TLR8 protein, mouse; D051200:Toll-Like Receptor 8
keywords: Apoptosis; Brain injury; Ischemic stroke; R848; TLR8