Xiangrong Liu1, Jia Liu1, Shangfeng Zhao1, Haiyue Zhang1, Wei Cai1, Mengfei Cai1, Xunming Ji1, Rehana K Leak1, Yanqin Gao1, Jun Chen1, Xiaoming Hu2. 1. 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.). 2. 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.
Abstract
BACKGROUND AND PURPOSE: 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.
BACKGROUND AND PURPOSE: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: Yvonne Nolan; Frank O Maher; Darren S Martin; Rachael M Clarke; Miriam T Brady; Anthony E Bolton; Kingston H G Mills; Marina A Lynch Journal: J Biol Chem Date: 2004-12-22 Impact factor: 5.157
Authors: H M Kim; H Y Shin; H J Jeong; H J An; N S Kim; H J Chae; H R Kim; H J Song; K Y Kim; S H Baek; K H Cho; B S Moon; Y M Lee Journal: J Mol Neurosci Date: 2000-06 Impact factor: 3.444
Authors: Noël C Derecki; Amber N Cardani; Chun Hui Yang; Kayla M Quinnies; Anastasia Crihfield; Kevin R Lynch; Jonathan Kipnis Journal: J Exp Med Date: 2010-05-03 Impact factor: 14.307
Authors: Mathias Gelderblom; Frank Leypoldt; Karin Steinbach; Doerthe Behrens; Chi-Un Choe; Dominic A Siler; Thiruma V Arumugam; Ellen Orthey; Christian Gerloff; Eva Tolosa; Tim Magnus Journal: Stroke Date: 2009-03-05 Impact factor: 7.914
Authors: Brett Kissela; Christopher J Lindsell; Dawn Kleindorfer; Kathleen Alwell; Charles J Moomaw; Daniel Woo; Matthew L Flaherty; Ellen Air; Joseph Broderick; Joel Tsevat Journal: Stroke Date: 2008-12-24 Impact factor: 7.914
Authors: Vivien Häußler; Tristan Daehn; Björn Rissiek; Vanessa Roth; Christian Gerloff; Thiruma V Arumugam; Tim Magnus; Mathias Gelderblom Journal: Neuromolecular Med Date: 2019-09-26 Impact factor: 3.843
Authors: Ping Sun; Kai Zhang; Sulaiman H Hassan; Xuejing Zhang; Xuelian Tang; Hongjian Pu; R Anne Stetler; Jun Chen; Ke-Jie Yin Journal: Circ Res Date: 2020-03-05 Impact factor: 17.367
Authors: Shenpeng R Zhang; Marius Piepke; Hannah X Chu; Brad Rs Broughton; Raymond Shim; Connie Hy Wong; Seyoung Lee; Megan A Evans; Antony Vinh; Samy Sakkal; Thiruma V Arumugam; Tim Magnus; Samuel Huber; Mathias Gelderblom; Grant R Drummond; Christopher G Sobey; Hyun Ah Kim Journal: JCI Insight Date: 2018-09-20
Authors: Alok Kumar; James P Barrett; Dulce-Mariely Alvarez-Croda; Bogdan A Stoica; Alan I Faden; David J Loane Journal: Brain Behav Immun Date: 2016-07-28 Impact factor: 7.217