title: ST2/IL-33-Dependent Microglial Response Limits Acute Ischemic Brain Injury.
abstract: ST2, a member of the interleukin (IL) 1 receptor family, and its ligand IL-33 play critical roles in immune regulation and inflammatory responses. This study explores the roles of endogenous IL-33/ST2 signaling in ischemic brain injury and elucidates the underlying mechanisms of action. The expression of IL-33 rapidly increased in oligodendrocytes and astrocytes after 60 min transient middle cerebral artery occlusion (tMCAO). ST2 receptor deficiency exacerbated brain infarction 3 d after tMCAO as well as distal permanent MCAO. ST2 deficiency also aggravated neurological deficits up to 7 d after tMCAO. Conversely, intracerebroventricular infusions of IL-33 after tMCAO attenuated brain infarction. Flow cytometry analyses demonstrated high levels of ST2 expression on microglia, and this expression was dramatically enhanced after tMCAO. The absence of ST2 enhanced the expression of M1 polarization markers on microglia/macrophages, and impaired the expression of M2 polarization markers after tMCAO.In vitrostudies on various types of cultures and coculture systems confirmed that IL-33/ST2 signaling potentiated expression ofIL-10and other M2 genes in primary microglia. The activation of ST2 on microglia led to a protective phenotype that enhanced neuronal survival against oxygen glucose deprivation. Furtherin vitrostudies revealed that IL-33-activated microglia released IL-10, and that this was critical for their neuroprotective effects. Similarly, intracerebroventricular infusions of IL-33 intoIL-10knock-out mice failed to provide neuroprotection against tMCAOin vivoThese results shed new light on the IL-33/ST2 axis as an immune regulatory mechanism that serves as a natural brake on the progression of ischemic brain injury.SIGNIFICANCE STATEMENTThis is the first study to identify the function of interleukin (IL) 33/ST2 signaling in poststroke microglial responses and neuroprotection against ischemia. Using two models of ischemic stroke, we demonstrate here that ST2 deficiency shifted microglia/macrophages toward a M1-like phenotype, thereby expanding brain infarcts and exacerbating long-term behavioral deficits after stroke. Using stroke models and variousin vitroculture and coculture systems, we further characterized a previously undefined mechanism whereby IL-33/ST2 engagement stimulates the production of IL-10 from microglia, which, in turn, enhances neuronal survival upon ischemic challenge. These results shed light on endogenous IL-33/ST2 signaling as a potential immune regulatory mechanism that serves to promote beneficial microglial responses and mitigate ischemic brain injury after stroke.
authors.affiliation: Pittsburgh Institute of Brain Disorders and Recovery, Department of Neurology and.|Xiangya Third Hospital, Central South University, Changsha, Hunan 410013, China.|Department of Neurology, Xiangya Hospital, Changsha, Hunan 410008, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Pittsburgh Institute of Brain Disorders and Recovery, Department of Neurology and.|Xiangya Third Hospital, Central South University, Changsha, Hunan 410013, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Pittsburgh Institute of Brain Disorders and Recovery, Department of Neurology and.|Xiangya Third Hospital, Central South University, Changsha, Hunan 410013, China.
authors.forename: Haiyue
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Pittsburgh Institute of Brain Disorders and Recovery, Department of Neurology and.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Pittsburgh Institute of Brain Disorders and Recovery, Department of Neurology and.|Xiangya Third Hospital, Central South University, Changsha, Hunan 410013, China.
authors.forename: Jianyi
authors.initials: J
authors.lastname: Wang
authors.affiliation: Pittsburgh Institute of Brain Disorders and Recovery, Department of Neurology and.
authors.forename: Boyu
authors.identifier: 0000-0001-8398-1753
authors.initials: B
authors.lastname: Yang
authors.affiliation: Pittsburgh Institute of Brain Disorders and Recovery, Department of Neurology and.
authors.forename: Leilei
authors.initials: L
authors.lastname: Mao
authors.affiliation: Pittsburgh Institute of Brain Disorders and Recovery, Department of Neurology and.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, and.
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
authors.affiliation: Department of Neurology, Xiangya Hospital, Changsha, Hunan 410008, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors.forename: Binfeng
authors.initials: B
authors.lastname: Lu
authors.affiliation: Pittsburgh Institute of Brain Disorders and Recovery, Department of Neurology and hux2@upmc.edu chenj2@upmc.edu.|Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania 15261.
authors.forename: Jun
authors.identifier: 0000-0002-8077-3403
authors.initials: J
authors.lastname: Chen
authors.affiliation: Pittsburgh Institute of Brain Disorders and Recovery, Department of Neurology and hux2@upmc.edu chenj2@upmc.edu.|Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania 15261.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology* / Q000473:pathology; D001930:Brain Injuries / Q000276:immunology* / Q000473:pathology; D002545:Brain Ischemia / Q000276:immunology* / Q000473:pathology; D005260:Female; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000276:immunology*; D000067596:Interleukin-33 / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology* / Q000473:pathology
chemical_list: C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33
keywords: IL-10; IL-33; ST2; microglia