title: Toll-like receptor 2/4 heterodimer mediates inflammatory injury in intracerebral hemorrhage.
abstract: OBJECTIVE
  Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)-induced secondary brain injury. However, the upstream events that initiate inflammatory responses following ICH remain elusive. Our previous studies suggested that Toll-like receptor 4 (TLR4) may be the upstream signal that triggers inflammatory injury in ICH. In addition, recent clinical findings indicated that both TLR2 and TLR4 may participate in ICH-induced brain injury. However, it is unclear how TLR2 functions in ICH-induced inflammatory injury and how TLR2 interacts with TLR4.
  
  
  METHODS
  The role of TLR2 and TLR2/TLR4 heterodimerization in ICH-induced inflammatory injury was investigated in both in vivo and in vitro models of ICH.
  
  
  RESULTS
  TLR2 mediated ICH-induced inflammatory injury, which forms a heterodimer with TLR4 in both in vivo and in vitro models of ICH. Hemoglobin (Hb), but not other blood components, triggered inflammatory injury in ICH via assembly of TLR2/TLR4 heterodimers. MyD88 (myeloid differentiation primary response gene 88), but not TRIF (Toll/IR-1 domain-containing adaptor protein inducing interferon-beta), was required for ICH-induced TLR2/TLR4 heterodimerization. Mutation of MyD88 Arg196 abolished the TLR2/TLR4 heterodimerization.
  
  
  CONCLUSIONS
  Our results suggest that a novel TLR2/TLR4 heterodimer induced by Hb initiates inflammatory injury in ICH. Interfering with the assembly of the TLR2/TLR4 heterodimer may be a novel target for developing effective treatment of ICH.
authors.affiliation: Department of Neurology, Xinqiao Hospital and Second Affiliated Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yan-Chun
authors.initials: YC
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Huang
authors.initials: H
authors.lastname: Fang
authors.forename: Sen
authors.initials: S
authors.lastname: Lin
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Wang
authors.forename: Ren-Ping
authors.initials: RP
authors.lastname: Xiong
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Xiong
authors.forename: Feng-Lin
authors.initials: FL
authors.lastname: Lv
authors.forename: Qiao-Li
authors.initials: QL
authors.lastname: Liang
authors.forename: Qing-Wu
authors.initials: QW
authors.lastname: Yang
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000175:diagnosis / Q000209:etiology; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000150:complications*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009422:Nervous System Diseases / Q000175:diagnosis / Q000209:etiology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2