The effect of fingolimod on regulatory T cells in a mouse model of brain ischaemia

dc.contributor.authorMalone, Kyle
dc.contributor.authorDiaz Diaz, Andrea C.
dc.contributor.authorShearer, Jennifer A.
dc.contributor.authorMoore, Anne C.
dc.contributor.authorWaeber, Christian
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderIrish Research Councilen
dc.contributor.funderHealth Research Boarden
dc.contributor.funderEuropean Commissionen
dc.date.accessioned2022-09-08T14:11:05Z
dc.date.available2022-09-08T14:11:05Z
dc.date.issued2021
dc.description.abstractBackground: The role of the immune system in stroke is well-recognised. Fingolimod, an immunomodulatory agent licensed for the management of relapsing-remitting multiple sclerosis, has been shown to provide benefit in rodent models of stroke. Its mechanism of action, however, remains unclear. We hypothesised fingolimod increases the number and/or function of regulatory T cells (Treg), a lymphocyte population which promotes stroke recovery. The primary aim of this study was to rigorously investigate the effect of fingolimod on Tregs in a mouse model of brain ischaemia. The effect of fingolimod in mice with common stroke-related comorbidities (ageing and hypercholesteremia) was also investigated. Methods: Young (15–17 weeks), aged C57BL/6 mice (72–73 weeks), and ApoE?/? mice fed a high-fat diet (20–21 weeks) underwent permanent electrocoagulation of the left middle cerebral artery. Mice received either saline or fingolimod (0.5 mg/kg or 1 mg/kg) at 2, 24, and 48 h post-ischaemia via intraperitoneal injection. Another cohort of young mice (8–9, 17–19 weeks) received short-term (5 days) or long-term (10 days) fingolimod (0.5 mg/kg) treatment. Flow cytometry was used to quantify Tregs in blood, spleen, and lymph nodes. Immunohistochemistry was used to quantify FoxP3+ cell infiltration into the ischaemic brain. Results: Fingolimod significantly increased the frequency of Tregs within the CD4+ T cell population in blood and spleen post-ischaemia in all three mouse cohorts compared to untreated ischemic mice. The highest splenic Treg frequency in fingolimod-treated mice was observed in ApoE?/? mice (9.32 ± 1.73% vs. 7.8 ± 3.01% in young, 6.09 ± 1.64% in aged mice). The highest circulating Treg frequency was also noted in ApoE?/? mice (8.39 ± 3.26% vs. 5.43 ± 2.74% in young, 4.56 ± 1.60% in aged mice). Fingolimod significantly increased the number of FoxP3+ cells in the infarct core of all mice. The most pronounced effects were seen when mice were treated for 10 days post-ischaemia. Conclusions: Fingolimod increases Treg frequency in spleen and blood post-ischaemia and enhances the number of FoxP3+ cells in the ischaemic brain. The effect of fingolimod on this regulatory cell population may underlie its neuroprotective activity and could be exploited as part of future stroke therapy.en
dc.description.sponsorshipIrish Research Council (grant number GOIPG/2017/431); Health Research Board (HRA-POR-2015-1236); European Commission (Interreg Atlantic Area Programme EAPA_791/2018, 2019–21); Science Foundation Ireland (BIAP2015)
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid37
dc.identifier.citationMalone, K., Diaz Diaz, A. C., Shearer, J. A., Moore, A. C. and Waeber, C. (2021) ‘The effect of fingolimod on regulatory T cells in a mouse model of brain ischaemia’, Journal of Neuroinflammation, 18(1), 37 (15pp). doi: 10.1186/s12974-021-02083-5en
dc.identifier.doi10.1186/s12974-021-02083-5
dc.identifier.endpage15
dc.identifier.issn17422094
dc.identifier.journaltitleJournal of Neuroinflammationen
dc.identifier.startpage1
dc.identifier.urihttps://hdl.handle.net/10468/13555
dc.language.isoenen
dc.publisherBioMed Central Ltden
dc.rights© 2021, the Authors. 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://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectFingolimoden
dc.subjectImmunomodulationen
dc.subjectIschaemiaen
dc.subjectNeuroinflammationen
dc.subjectRegulatory T cellsen
dc.subjectStrokeen
dc.titleThe effect of fingolimod on regulatory T cells in a mouse model of brain ischaemiaen
dc.typeArticle (peer-reviewed)en
Files
Original bundle
Now showing 1 - 2 of 2
Loading...
Thumbnail Image
Name:
s12974-021-02083-5.pdf
Size:
2.38 MB
Format:
Adobe Portable Document Format
Description:
Published Version
Loading...
Thumbnail Image
Name:
13669402.zip
Size:
322.72 KB
Format:
http://www.iana.org/assignments/media-types/application/zip
Description:
Supplementary Information