Interleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response

Abstract Background Lymphocytes have dichotomous functions in ischemic stroke. Regulatory T cells are protective, while IL-17A from innate lymphocytes promotes the infarct growth. With recent advances of T cell-subtype specific transgenic mouse models it now has become possible to study the complex...

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Autores principales:	Marius Piepke, Bettina H. Clausen, Peter Ludewig, Jonas H. Vienhues, Tanja Bedke, Ehsan Javidi, Björn Rissiek, Larissa Jank, Leonie Brockmann, Inga Sandrock, Karoline Degenhardt, Alina Jander, Vanessa Roth, Ines S. Schädlich, Immo Prinz, Richard A. Flavell, Yasushi Kobayashi, Thomas Renné, Christian Gerloff, Samuel Huber, Tim Magnus, Mathias Gelderblom
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Stroke Ischemia Inflammation T cells Interleukin-10 Interleukin-17 Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/84eccf40e2484f5c8eb8bfa924fd98ed
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spelling	oai:doaj.org-article:84eccf40e2484f5c8eb8bfa924fd98ed2021-11-14T12:38:04ZInterleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response10.1186/s12974-021-02316-71742-2094https://doaj.org/article/84eccf40e2484f5c8eb8bfa924fd98ed2021-11-01T00:00:00Zhttps://doi.org/10.1186/s12974-021-02316-7https://doaj.org/toc/1742-2094Abstract Background Lymphocytes have dichotomous functions in ischemic stroke. Regulatory T cells are protective, while IL-17A from innate lymphocytes promotes the infarct growth. With recent advances of T cell-subtype specific transgenic mouse models it now has become possible to study the complex interplay of T cell subpopulations in ischemic stroke. Methods In a murine model of experimental stroke we analyzed the effects of IL-10 on the functional outcome for up to 14 days post-ischemia and defined the source of IL-10 in ischemic brains based on immunohistochemistry, flow cytometry, and bone-marrow chimeric mice. We used neutralizing IL-17A antibodies, intrathecal IL-10 injections, and transgenic mouse models which harbor a deletion of the IL-10R on distinct T cell subpopulations to further explore the interplay between IL-10 and IL-17A pathways in the ischemic brain. Results We demonstrate that IL-10 deficient mice exhibit significantly increased infarct sizes on days 3 and 7 and enlarged brain atrophy and impaired neurological outcome on day 14 following tMCAO. In ischemic brains IL-10 producing immune cells included regulatory T cells, macrophages, and microglia. Neutralization of IL-17A following stroke reversed the worse outcome in IL-10 deficient mice and intracerebral treatment with recombinant IL-10 revealed that IL-10 controlled IL-17A positive lymphocytes in ischemic brains. Importantly, IL-10 acted differentially on αβ and γδ T cells. IL-17A producing CD4+ αβ T cells were directly controlled via their IL-10-receptor (IL-10R), whereas IL-10 by itself had no direct effect on the IL-17A production in γδ T cells. The control of the IL-17A production in γδ T cells depended on an intact IL10R signaling in regulatory T cells (Tregs). Conclusions Taken together, our data indicate a key function of IL-10 in restricting the detrimental IL-17A-signaling in stroke and further supports that IL-17A is a therapeutic opportunity for stroke treatment.Marius PiepkeBettina H. ClausenPeter LudewigJonas H. VienhuesTanja BedkeEhsan JavidiBjörn RissiekLarissa JankLeonie BrockmannInga SandrockKaroline DegenhardtAlina JanderVanessa RothInes S. SchädlichImmo PrinzRichard A. FlavellYasushi KobayashiThomas RennéChristian GerloffSamuel HuberTim MagnusMathias GelderblomBMCarticleStrokeIschemiaInflammationT cellsInterleukin-10Interleukin-17Neurology. Diseases of the nervous systemRC346-429ENJournal of Neuroinflammation, Vol 18, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Stroke Ischemia Inflammation T cells Interleukin-10 Interleukin-17 Neurology. Diseases of the nervous system RC346-429
spellingShingle	Stroke Ischemia Inflammation T cells Interleukin-10 Interleukin-17 Neurology. Diseases of the nervous system RC346-429 Marius Piepke Bettina H. Clausen Peter Ludewig Jonas H. Vienhues Tanja Bedke Ehsan Javidi Björn Rissiek Larissa Jank Leonie Brockmann Inga Sandrock Karoline Degenhardt Alina Jander Vanessa Roth Ines S. Schädlich Immo Prinz Richard A. Flavell Yasushi Kobayashi Thomas Renné Christian Gerloff Samuel Huber Tim Magnus Mathias Gelderblom Interleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response
description	Abstract Background Lymphocytes have dichotomous functions in ischemic stroke. Regulatory T cells are protective, while IL-17A from innate lymphocytes promotes the infarct growth. With recent advances of T cell-subtype specific transgenic mouse models it now has become possible to study the complex interplay of T cell subpopulations in ischemic stroke. Methods In a murine model of experimental stroke we analyzed the effects of IL-10 on the functional outcome for up to 14 days post-ischemia and defined the source of IL-10 in ischemic brains based on immunohistochemistry, flow cytometry, and bone-marrow chimeric mice. We used neutralizing IL-17A antibodies, intrathecal IL-10 injections, and transgenic mouse models which harbor a deletion of the IL-10R on distinct T cell subpopulations to further explore the interplay between IL-10 and IL-17A pathways in the ischemic brain. Results We demonstrate that IL-10 deficient mice exhibit significantly increased infarct sizes on days 3 and 7 and enlarged brain atrophy and impaired neurological outcome on day 14 following tMCAO. In ischemic brains IL-10 producing immune cells included regulatory T cells, macrophages, and microglia. Neutralization of IL-17A following stroke reversed the worse outcome in IL-10 deficient mice and intracerebral treatment with recombinant IL-10 revealed that IL-10 controlled IL-17A positive lymphocytes in ischemic brains. Importantly, IL-10 acted differentially on αβ and γδ T cells. IL-17A producing CD4+ αβ T cells were directly controlled via their IL-10-receptor (IL-10R), whereas IL-10 by itself had no direct effect on the IL-17A production in γδ T cells. The control of the IL-17A production in γδ T cells depended on an intact IL10R signaling in regulatory T cells (Tregs). Conclusions Taken together, our data indicate a key function of IL-10 in restricting the detrimental IL-17A-signaling in stroke and further supports that IL-17A is a therapeutic opportunity for stroke treatment.
format	article
author	Marius Piepke Bettina H. Clausen Peter Ludewig Jonas H. Vienhues Tanja Bedke Ehsan Javidi Björn Rissiek Larissa Jank Leonie Brockmann Inga Sandrock Karoline Degenhardt Alina Jander Vanessa Roth Ines S. Schädlich Immo Prinz Richard A. Flavell Yasushi Kobayashi Thomas Renné Christian Gerloff Samuel Huber Tim Magnus Mathias Gelderblom
author_facet	Marius Piepke Bettina H. Clausen Peter Ludewig Jonas H. Vienhues Tanja Bedke Ehsan Javidi Björn Rissiek Larissa Jank Leonie Brockmann Inga Sandrock Karoline Degenhardt Alina Jander Vanessa Roth Ines S. Schädlich Immo Prinz Richard A. Flavell Yasushi Kobayashi Thomas Renné Christian Gerloff Samuel Huber Tim Magnus Mathias Gelderblom
author_sort	Marius Piepke
title	Interleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response
title_short	Interleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response
title_full	Interleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response
title_fullStr	Interleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response
title_full_unstemmed	Interleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response
title_sort	interleukin-10 improves stroke outcome by controlling the detrimental interleukin-17a response
publisher	BMC
publishDate	2021
url	https://doaj.org/article/84eccf40e2484f5c8eb8bfa924fd98ed
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Interleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response

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