title: Immunomodulation by interleukin-33 is protective in stroke through modulation of inflammation.
abstract: Cerebral stroke induces massive Th1-shifted inflammation both in the brain and the periphery, contributing to the outcome of stroke. A Th1-type response is neurotoxic whereas a Th2-type response is accompanied by secretion of anti-inflammatory cytokines, such as interleukin-4 (IL-4). Interleukin-33 (IL-33) is a cytokine known to induce a shift towards the Th2-type immune response, polarize macrophages/microglia towards the M2-type, and induce production of anti-inflammatory cytokines. We found that the plasma levels of the inhibitory IL-33 receptor, sST2, are increased in human stroke and correlate with a worsened stroke outcome, suggesting an insufficient IL-33-driven Th2-type response. In mouse, peripheral administration of IL-33 reduced stroke-induced cell death and improved the sensitivity of the contralateral front paw at 5days post injury. The IL-33-treated mice had increased levels of IL-4 in the spleen and in the peri-ischemic area of the cortex. Neutralization of IL-4 by administration of an IL-4 antibody partially prevented the IL-33-mediated protection. IL-33 treatment also reduced astrocytic activation in the peri-ischemic area and increased the number of Arginase-1 immunopositive microglia/macrophages at the lesion site. In human T-cells, IL-33 treatment induced IL-4 secretion, and the conditioned media from IL-33-exposed T-cells reduced astrocytic activation. This study demonstrates that IL-33 is protective against ischemic insult by induction of IL-4 secretion and may represent a novel therapeutic approach for the treatment of stroke.
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Paula
authors.initials: P
authors.lastname: Korhonen
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Katja M
authors.initials: KM
authors.lastname: Kanninen
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Šárka
authors.initials: Š
authors.lastname: Lehtonen
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Sighild
authors.initials: S
authors.lastname: Lemarchant
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Katja A
authors.initials: KA
authors.lastname: Puttonen
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Oksanen
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Hiramani
authors.initials: H
authors.lastname: Dhungana
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Loppi
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Eveliina
authors.initials: E
authors.lastname: Pollari
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Sara
authors.initials: S
authors.lastname: Wojciechowski
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Iurii
authors.initials: I
authors.lastname: Kidin
authors.affiliation: Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Pg. Vall d'Hebron, 119-129, 08035 Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: García-Berrocoso
authors.affiliation: Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Pg. Vall d'Hebron, 119-129, 08035 Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Giralt
authors.affiliation: Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. Electronic address: jari.koistinaho@uef.fi.
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
authors.affiliation: Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Malm
mesh_terms: D000368:Aged; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002545:Brain Ischemia / Q000097:blood / Q000276:immunology* / Q000517:prevention & control*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control*; D000067596:Interleukin-33 / Q000008:administration & dosage / Q000097:blood*; D015847:Interleukin-4 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects / Q000276:immunology; D009043:Motor Activity / Q000187:drug effects; D017481:Receptors, Somatostatin / Q000097:blood*; D011994:Recombinant Proteins / Q000008:administration & dosage; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020521:Stroke / Q000097:blood / Q000276:immunology* / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D016207:Cytokines; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D017481:Receptors, Somatostatin; D011994:Recombinant Proteins; D015847:Interleukin-4
keywords: Cerebral stroke; Cytokines; Inflammation; Interleukin; Peripheral immune system