title: The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice.
abstract: TIR domain-containing adaptor protein (TRIF) is an adaptor protein in Toll-like receptor (TLR) signaling pathways. Activation of TRIF leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-kappaB). While studies have shown that TLRs are implicated in cerebral ischemia/reperfusion (I/R) injury and in neuroprotection against ischemia afforded by preconditioning, little is known about TRIF's role in the pathological process following cerebral I/R. The present study investigated the role that TRIF may play in acute cerebral I/R injury. In a mouse model of cerebral I/R induced by transient middle cerebral artery occlusion, we examined the activation of NF-kappaB and IRF3 signaling in ischemic cerebral tissue using ELISA and Western blots. Neurological function and cerebral infarct size were also evaluated 24h after cerebral I/R. NF-kappaB activity and phosphorylation of the inhibitor of kappa B (IkappaBalpha) increased in ischemic brains, but IRF3, inhibitor of kappaB kinase complex-epsilon (IKKepsilon), and TANK-binding kinase1 (TBK1) were not activated after cerebral I/R in wild-type (WT) mice. Interestingly, TRIF deficit did not inhibit NF-kappaB activity or p-IkappaBalpha induced by cerebral I/R. Moreover, although cerebral I/R induced neurological and functional impairments and brain infarction in WT mice, the deficits were not improved and brain infarct size was not reduced in TRIF knockout mice compared to WT mice. Our results demonstrate that the TRIF-dependent signaling pathway is not required for the activation of NF-kappaB signaling and brain injury after acute cerebral I/R.
authors.affiliation: Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, Atlanta, GA 30322, USA. fhua2@emory.edu
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Iqbal
authors.initials: I
authors.lastname: Sayeed
authors.forename: Tauheed
authors.initials: T
authors.lastname: Ishrat
authors.forename: Fahim
authors.initials: F
authors.lastname: Atif
authors.forename: Donald G
authors.initials: DG
authors.lastname: Stein
mesh_terms: D000208:Acute Disease; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051550:I-kappa B Kinase / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D051550:I-kappa B Kinase; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C476286:Ticam1 protein, mouse; C498588:Tbk1 protein, mouse; C496564:Chuk protein, mouse