Piepke et al. Journal of Neuroinflammation (2021) 18:265 https://doi.org/10.1186/s12974-021-02316-7 RESEARCH Interleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response Marius Piepke 1 , Bettina H. Clausen 2 , Peter Ludewig 1 , Jonas H. Vienhues 1 , Tanja Bedke 3 , Ehsan Javidi 1 , Björn Rissiek 1 , Larissa Jank 1 , Leonie Brockmann 3 , Inga Sandrock 4 , Karoline Degenhardt 1 , Alina Jander 1 , Vanessa Roth 1 , Ines S. Schädlich 1 , Immo Prinz 5 , Richard A. Flavell 6 , Yasushi Kobayashi 6 , Thomas Renné 7 , Christian Gerloff 1 , Samuel Huber 3 , Tim Magnus 1 and Mathias Gelderblom 1* 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 trans- genic 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 follow- ing 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. Keywords: Stroke, Ischemia, Inflammation, T cells, Interleukin-10, Interleukin-17 © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Background Worldwide, stroke is one of the leading causes of mortal- ity and sustained disability, with 5.5 million deaths and 11 million disability-adjusted life-years in 2016 [1]. Inflammation is a key component of stroke pathophysi- ology, with dichotomous effects on the affected tissue. Open Access *Correspondence: m.gelderblom@uke.de 1 Department of Neurology, University Medical Center Hamburg- Eppendorf, Martinistraße 52, 20246 Hamburg, Germany Full list of author information is available at the end of the article