Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke

The devastating effect of ischemic stroke is attenuated in mice lacking conventional and unconventional T cells, suggesting that inflammation enhances tissue damage in cerebral ischemia. We explored the functional role of αβ and γδ T cells in a murine model of stroke and distinguished 2 different T...

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Published in:	Blood Vol. 120; no. 18; pp. 3793 - 3802
Main Authors:	Gelderblom, Mathias, Weymar, Anna, Bernreuther, Christian, Velden, Joachim, Arunachalam, Priyadharshini, Steinbach, Karin, Orthey, Ellen, Arumugam, Thiruma V., Leypoldt, Frank, Simova, Olga, Thom, Vivien, Friese, Manuel A., Prinz, Immo, Hölscher, Christoph, Glatzel, Markus, Korn, Thomas, Gerloff, Christian, Tolosa, Eva, Magnus, Tim
Format:	Journal Article
Language:	English
Published:	Washington, DC Elsevier Inc 01-11-2012 Americain Society of Hematology
Subjects:	Animals Biological and medical sciences Brain Ischemia - immunology Brain Ischemia - metabolism Disease Models, Animal Enzyme-Linked Immunosorbent Assay Flow Cytometry Hematologic and hematopoietic diseases Humans Immunohistochemistry Interleukin-17 - immunology Interleukin-17 - metabolism Medical sciences Mice Mice, Inbred C57BL Mice, Transgenic Neurology Neutrophil Infiltration - immunology Neutrophils - immunology Real-Time Polymerase Chain Reaction Signal Transduction - immunology Stroke - immunology Stroke - metabolism T-Lymphocytes - immunology T-Lymphocytes - metabolism Vascular diseases and vascular malformations of the nervous system Cerebral infarction Nervous system diseases Stroke Hematology Granulocyte Cardiovascular disease Malignant tumor Metastasis Interleukin 17 Invasion Cerebral disorder Vascular disease Central nervous system disease Brain ischemia Neutrophil Cerebrovascular disease Cancer Neutralization
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Summary:	The devastating effect of ischemic stroke is attenuated in mice lacking conventional and unconventional T cells, suggesting that inflammation enhances tissue damage in cerebral ischemia. We explored the functional role of αβ and γδ T cells in a murine model of stroke and distinguished 2 different T cell–dependent proinflammatory pathways in ischemia-reperfusion injury. IFN-γ produced by CD4+ T cells induced TNF-α production in macrophages, whereas IL-17A secreted by γδ T cells led to neutrophil recruitment. The synergistic effect of TNF-α and IL-17A on astrocytes resulted in enhanced secretion of CXCL-1, a neutrophil chemoattractant. Application of an IL-17A–blocking antibody within 3 hours after stroke induction decreased infarct size and improved neurologic outcome in the murine model. In autoptic brain tissue of patients who had a stroke, we detected IL-17A–positive lymphocytes, suggesting that this aspect of the inflammatory cascade is also relevant in the human brain. We propose that selective targeting of IL-17A signaling might provide a new therapeutic option for the treatment of stroke.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0006-4971 1528-0020
DOI:	10.1182/blood-2012-02-412726