title: Interleukin-4 Is Essential for Microglia/Macrophage M2 Polarization and Long-Term Recovery After Cerebral Ischemia.
abstract: OBJECTIVE
  Interleukin-4 (IL-4) is a unique cytokine that may contribute to brain repair by regulating microglia/macrophage functions. Thus, we examined the effect of IL-4 on long-term recovery and microglia/macrophage polarization in 2 well-established stroke models.
  
  
  METHODS
  Transient middle cerebral artery occlusion or permanent distal middle cerebral artery occlusion was induced in wild-type and IL-4 knockout C57/BL6 mice. In a separate cohort of wild-type animals, IL-4 (60 ng/d for 7 days) or vehicle was infused into the cerebroventricle after transient middle cerebral artery occlusion. Behavioral outcomes were assessed by the Rotarod, corner, foot fault, and Morris water maze tests. Neuronal tissue loss was verified by 2 independent neuron markers. Markers of classically activated (M1) and alternatively activated (M2) microglia were assessed by real-time polymerase chain reaction, immunofluorescence, and flow cytometry.
  
  
  RESULTS
  Loss of IL-4 exacerbated sensorimotor deficits and impaired cognitive functions ≤21 days post injury. In contrast to the delayed deterioration of neurological functions, IL-4 deficiency increased neuronal tissue loss only in the acute phase (5 days) after stroke and had no impact on neuronal tissue loss 14 or 21 days post injury. Loss of IL-4 promoted expression of M1 microglia/macrophage markers and impaired expression of M2 markers at 5 and 14 days post injury. Administration of IL-4 into the ischemic brain also enhanced long-term functional recovery.
  
  
  CONCLUSIONS
  The cytokine IL-4 improves long-term neurological outcomes after stroke, perhaps through M2 phenotype induction in microglia/macrophages. These results are the first to suggest that immunomodulation with IL-4 is a promising approach to promote long-term functional recovery after stroke.
authors.affiliation: From the Department of Neurology, University of Pittsburgh School of Medicine, PA (X.L., S.Z., H.Z., W.C., J.C., X.H.); Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, P.R. China (X.L., X.J.); State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., M.C., Y.G., J.C., X.H.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, PA (J.C., X.H.).
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Liu
authors.affiliation: From the Department of Neurology, University of Pittsburgh School of Medicine, PA (X.L., S.Z., H.Z., W.C., J.C., X.H.); Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, P.R. China (X.L., X.J.); State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., M.C., Y.G., J.C., X.H.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, PA (J.C., X.H.).
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: From the Department of Neurology, University of Pittsburgh School of Medicine, PA (X.L., S.Z., H.Z., W.C., J.C., X.H.); Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, P.R. China (X.L., X.J.); State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., M.C., Y.G., J.C., X.H.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, PA (J.C., X.H.).
authors.forename: Shangfeng
authors.initials: S
authors.lastname: Zhao
authors.affiliation: From the Department of Neurology, University of Pittsburgh School of Medicine, PA (X.L., S.Z., H.Z., W.C., J.C., X.H.); Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, P.R. China (X.L., X.J.); State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., M.C., Y.G., J.C., X.H.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, PA (J.C., X.H.).
authors.forename: Haiyue
authors.initials: H
authors.lastname: Zhang
authors.affiliation: From the Department of Neurology, University of Pittsburgh School of Medicine, PA (X.L., S.Z., H.Z., W.C., J.C., X.H.); Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, P.R. China (X.L., X.J.); State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., M.C., Y.G., J.C., X.H.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, PA (J.C., X.H.).
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
authors.affiliation: From the Department of Neurology, University of Pittsburgh School of Medicine, PA (X.L., S.Z., H.Z., W.C., J.C., X.H.); Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, P.R. China (X.L., X.J.); State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., M.C., Y.G., J.C., X.H.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, PA (J.C., X.H.).
authors.forename: Mengfei
authors.initials: M
authors.lastname: Cai
authors.affiliation: From the Department of Neurology, University of Pittsburgh School of Medicine, PA (X.L., S.Z., H.Z., W.C., J.C., X.H.); Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, P.R. China (X.L., X.J.); State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., M.C., Y.G., J.C., X.H.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, PA (J.C., X.H.).
authors.forename: Xunming
authors.initials: X
authors.lastname: Ji
authors.affiliation: From the Department of Neurology, University of Pittsburgh School of Medicine, PA (X.L., S.Z., H.Z., W.C., J.C., X.H.); Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, P.R. China (X.L., X.J.); State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., M.C., Y.G., J.C., X.H.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, PA (J.C., X.H.).
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
authors.affiliation: From the Department of Neurology, University of Pittsburgh School of Medicine, PA (X.L., S.Z., H.Z., W.C., J.C., X.H.); Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, P.R. China (X.L., X.J.); State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., M.C., Y.G., J.C., X.H.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, PA (J.C., X.H.).
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
authors.affiliation: From the Department of Neurology, University of Pittsburgh School of Medicine, PA (X.L., S.Z., H.Z., W.C., J.C., X.H.); Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, P.R. China (X.L., X.J.); State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., M.C., Y.G., J.C., X.H.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, PA (J.C., X.H.).
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: From the Department of Neurology, University of Pittsburgh School of Medicine, PA (X.L., S.Z., H.Z., W.C., J.C., X.H.); Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, P.R. China (X.L., X.J.); State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., M.C., Y.G., J.C., X.H.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, PA (J.C., X.H.). hux2@upmc.edu.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002545:Brain Ischemia / Q000235:genetics / Q000276:immunology*; D057967:Infusions, Intraventricular; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000276:immunology*; D009483:Neuropsychological Tests; D012333:RNA, Messenger / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology*; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D000276:Adjuvants, Immunologic; D015847:Interleukin-4; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit
keywords: flow cytometry; interleukin-4; macrophages; neurological function; stroke