title: MyD88 contributes to neuroinflammatory responses induced by cerebral ischemia/reperfusion in mice.
abstract: Myeloid differentiation primary-response protein-88 (MyD88) is one of adaptor proteins mediating Toll-like receptors (TLRs) signaling. Activation of MyD88 results in the activation of nuclear factor kappa B (NFκB) and the increase of inflammatory responses. Evidences have demonstrated that TLRs signaling contributes to cerebral ischemia/reperfusion (I/R) injury. However, the role of MyD88 in this mechanism of action is disputed and needs to be clarified. In the present study, in a mouse model of cerebral I/R, we examined the activities of NFκB and interferon factor-3 (IRF3), and the inflammatory responses in ischemic brain tissue using ELISA, Western blots, and real-time PCR. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. Our results showed that NFκB activity increased in ischemic brains, but IRF3 was not activated after cerebral I/R, in wild-type (WT) mice. MyD88 deficit inhibited the activation of NFκB, and the expression of interleukin-1β (IL-1β), IL-6, Beclin-1 (BECN1), pellino-1, and cyclooxygenase-2 (COX-2) increased by cerebral I/R compared with WT mice. Interestingly, the expression of interferon Beta 1 (INFB1) and vascular endothelial growth factor (VEGF) increased in MyD88 KO mice. Unexpectedly, although the neurological function improved in the MyD88 knockout (KO) mice, the deficit of MyD88 failed to reduce cerebral infarct size compared to WT mice. We concluded that MyD88-dependent signaling contributes to the inflammatory responses induced by cerebral I/R. MyD88 deficit may inhibit the increased inflammatory response and increase neuroprotective signaling.
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
authors.forename: Delian
authors.initials: D
authors.lastname: Kong
authors.affiliation: Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Tauheed
authors.initials: T
authors.lastname: Ishrat
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Shenyang Medical College, Shenyang, 110000, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
authors.forename: Guiyun
authors.initials: G
authors.lastname: Cui
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China; Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA; Key Laboratory of Anesthesiology of Jiangsu Province, Xuzhou 221002, China. Electronic address: huafang@xzhmu.edu.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
mesh_terms: D000818:Animals; D000071186:Beclin-1 / Q000378:metabolism; D015153:Blotting, Western; D020520:Brain Infarction / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004660:Encephalitis / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D000071186:Beclin-1; C115010:Becn1 protein, mouse; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
keywords: Cerebral ischemia/reperfusion injury; Inflammatory responses; MyD88-dependent pathway; Toll-like receptors