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      Critical role of astrocytic interleukin-17 A in post-stroke survival and neuronal differentiation of neural precursor cells in adult mice

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          Abstract

          The brain and the immune system interact in complex ways after ischemic stroke, and the long-term effects of immune response associated with stroke remain controversial. As a linkage between innate and adaptive immunity, interleukin-17 A (IL-17 A) secreted from gamma delta (γδ) T cells has detrimental roles in the pathogenesis of acute ischemic stroke. However, to date, the long-term actions of IL-17 A after stroke have not been investigated. Here, we found that IL-17 A showed two distinct peaks of expression in the ischemic hemisphere: the first occurring within 3 days and the second on day 28 after stroke. Our data also showed that astrocyte was the major cellular source of IL-17 A that maintained and augmented subventricular zone (SVZ) neural precursor cells (NPCs) survival, neuronal differentiation, and subsequent synaptogenesis and functional recovery after stroke. IL-17 A also promoted neuronal differentiation in cultured NPCs from the ischemic SVZ. Furthermore, our in vitro data revealed that in primary astrocyte cultures activated astrocytes released IL-17 A via p38 mitogen-activated protein kinase (MAPK). Culture media from reactive astrocytes increased neuronal differentiation of NSCs in vitro. Blockade of IL-17 A with neutralizing antibody prevented this effect. In addition, after screening for multiple signaling pathways, we revealed that the p38 MAPK/calpain 1 signaling pathway was involved in IL-17 A-mediated neurogenesis in vivo and in vitro. Thus, our results reveal a previously uncharacterized property of astrocytic IL-17 A in the maintenance and augment of survival and neuronal differentiation of NPCs, and subsequent synaptogenesis and spontaneous recovery after ischemic stroke.

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          Most cited references39

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          Neuronal replacement from endogenous precursors in the adult brain after stroke.

          In the adult brain, new neurons are continuously generated in the subventricular zone and dentate gyrus, but it is unknown whether these neurons can replace those lost following damage or disease. Here we show that stroke, caused by transient middle cerebral artery occlusion in adult rats, leads to a marked increase of cell proliferation in the subventricular zone. Stroke-generated new neurons, as well as neuroblasts probably already formed before the insult, migrate into the severely damaged area of the striatum, where they express markers of developing and mature, striatal medium-sized spiny neurons. Thus, stroke induces differentiation of new neurons into the phenotype of most of the neurons destroyed by the ischemic lesion. Here we show that the adult brain has the capacity for self-repair after insults causing extensive neuronal death. If the new neurons are functional and their formation can be stimulated, a novel therapeutic strategy might be developed for stroke in humans.
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            Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury.

            Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that gammadeltaT lymphocytes, but not CD4(+) helper T cells, were a major source of IL-17. Moreover, depletion of gammadeltaT lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including gammadeltaT lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.
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              Stroke.

              Stroke is the second most common cause of death and major cause of disability worldwide. Because of the ageing population, the burden will increase greatly during the next 20 years, especially in developing countries. Advances have occurred in the prevention and treatment of stroke during the past decade. For patients with acute stroke, management in a stroke care unit, intravenous tissue plasminogen activator within 3 h or aspirin within 48 h of stroke onset, and decompressive surgery for supratentorial malignant hemispheric cerebral infarction are interventions of proven benefit; several other interventions are being assessed. Proven secondary prevention strategies are warfarin for patients with atrial fibrillation, endarterectomy for symptomatic carotid stenosis, antiplatelet agents, and cholesterol reduction. The most important intervention is the management of patients in stroke care units because these provide a framework within which further study might be undertaken. These advances have exposed a worldwide shortage of stroke health-care workers, especially in developing countries.
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                Author and article information

                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group
                2041-4889
                June 2016
                23 June 2016
                1 June 2016
                : 7
                : 6
                : e2273
                Affiliations
                [1 ]Department of Anesthesia, Institute of Anesthesia and Critical Care, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China
                [2 ]Department of Critical Care Medicine, Institute of Anesthesia and Critical Care, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China
                [3 ]Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China
                [4 ]Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China
                [5 ]Department of Anesthesia, Faculty of Medicine, Benha University , Benha, Egypt
                Author notes
                [* ]Departments of Anesthesia and Critical Care Medicine, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , 1277 Jiefang Avenue, Wuhan 430022, China. Tel/Fax: +86 027 85351660; E-mail: ysltian@ 123456163.com
                [* ]Departments of Anesthesia and Critical Care Medicine, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , 1277 Jiefang Avenue, Wuhan 430022, China. Tel/Fax: +86 027 85351660; E-mail: yuan_shiying@ 123456163.com
                [6]

                Yun Lin, Jian-Cheng Zhang and Cheng-Ye Yao are co-first authors.

                [7]

                These authors contributed equally to this work.

                Article
                cddis2015284
                10.1038/cddis.2015.284
                5143370
                27336717
                b0394e57-b533-493b-a741-88dbaa6a777f
                Copyright © 2016 Macmillan Publishers Limited

                Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 20 April 2015
                : 06 July 2015
                : 02 September 2015
                Categories
                Original Article

                Cell biology
                Cell biology

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