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

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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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12974-021-02316-7.

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Most cited references 39

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Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Valery L. Feigin, Emma Nichols, Tahiya Alam … (2020)

Summary Background Neurological disorders are increasingly recognised as major causes of death and disability worldwide. The aim of this analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 is to provide the most comprehensive and up-to-date estimates of the global, regional, and national burden from neurological disorders. Methods We estimated prevalence, incidence, deaths, and disability-adjusted life-years (DALYs; the sum of years of life lost [YLLs] and years lived with disability [YLDs]) by age and sex for 15 neurological disorder categories (tetanus, meningitis, encephalitis, stroke, brain and other CNS cancers, traumatic brain injury, spinal cord injury, Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis, motor neuron diseases, idiopathic epilepsy, migraine, tension-type headache, and a residual category for other less common neurological disorders) in 195 countries from 1990 to 2016. DisMod-MR 2.1, a Bayesian meta-regression tool, was the main method of estimation of prevalence and incidence, and the Cause of Death Ensemble model (CODEm) was used for mortality estimation. We quantified the contribution of 84 risks and combinations of risk to the disease estimates for the 15 neurological disorder categories using the GBD comparative risk assessment approach. Findings Globally, in 2016, neurological disorders were the leading cause of DALYs (276 million [95% UI 247–308]) and second leading cause of deaths (9·0 million [8·8–9·4]). The absolute number of deaths and DALYs from all neurological disorders combined increased (deaths by 39% [34–44] and DALYs by 15% [9–21]) whereas their age-standardised rates decreased (deaths by 28% [26–30] and DALYs by 27% [24–31]) between 1990 and 2016. The only neurological disorders that had a decrease in rates and absolute numbers of deaths and DALYs were tetanus, meningitis, and encephalitis. The four largest contributors of neurological DALYs were stroke (42·2% [38·6–46·1]), migraine (16·3% [11·7–20·8]), Alzheimer's and other dementias (10·4% [9·0–12·1]), and meningitis (7·9% [6·6–10·4]). For the combined neurological disorders, age-standardised DALY rates were significantly higher in males than in females (male-to-female ratio 1·12 [1·05–1·20]), but migraine, multiple sclerosis, and tension-type headache were more common and caused more burden in females, with male-to-female ratios of less than 0·7. The 84 risks quantified in GBD explain less than 10% of neurological disorder DALY burdens, except stroke, for which 88·8% (86·5–90·9) of DALYs are attributable to risk factors, and to a lesser extent Alzheimer's disease and other dementias (22·3% [11·8–35·1] of DALYs are risk attributable) and idiopathic epilepsy (14·1% [10·8–17·5] of DALYs are risk attributable). Interpretation Globally, the burden of neurological disorders, as measured by the absolute number of DALYs, continues to increase. As populations are growing and ageing, and the prevalence of major disabling neurological disorders steeply increases with age, governments will face increasing demand for treatment, rehabilitation, and support services for neurological disorders. The scarcity of established modifiable risks for most of the neurological burden demonstrates that new knowledge is required to develop effective prevention and treatment strategies. Funding Bill & Melinda Gates Foundation.

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A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival.

Peggy Lee, David FitzPatrick, Caroline Beard … (2001)

The role of DNA methylation and of the maintenance DNA methyltransferase Dnmt1 in the epigenetic regulation of developmental stage- and cell lineage-specific gene expression in vivo is uncertain. This is addressed here through the generation of mice in which Dnmt1 was inactivated by Cre/loxP-mediated deletion at sequential stages of T cell development. Deletion of Dnmt1 in early double-negative thymocytes led to impaired survival of TCRalphabeta(+) cells and the generation of atypical CD8(+)TCRgammadelta(+) cells. Deletion of Dnmt1 in double-positive thymocytes impaired activation-induced proliferation but differentially enhanced cytokine mRNA expression by naive peripheral T cells. We conclude that Dnmt1 and DNA methylation are required for the proper expression of certain genes that define fate and determine function in T cells.

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The immunology of stroke: from mechanisms to translation

Costantino Iadecola, Josef Anrather (2011)

Immunity and inflammation are key elements of the pathobiology of stroke, a devastating illness second only to cardiac ischemia as a cause of death worldwide. While the immune system participates in the brain damage produced by ischemia, the damaged brain, in turn, exerts a powerful immunosuppressive effect that promotes fatal intercurrent infections and threatens the survival of stroke patients. Inflammatory signaling is instrumental in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion, to the late regenerative processes underlying post-ischemic tissue repair. Recent developments have revealed that stroke, like multiple sclerosis, engages both innate and adaptive immunity. But, unlike multiple sclerosis, adaptive immunity triggered by newly exposed brain antigens does not have an impact on the acute phase of the damage. Nevertheless, modulation of adaptive immunity exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. However, immunomodulation is not devoid of deleterious side effects, and gaining a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.

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Author and article information

Contributors

Mathias Gelderblom: m.gelderblom@uke.de

Journal

Journal ID (nlm-ta): J Neuroinflammation

Journal ID (iso-abbrev): J Neuroinflammation

Title: Journal of Neuroinflammation

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-2094

Publication date (Electronic): 13 November 2021

Publication date PMC-release: 13 November 2021

Publication date Collection: 2021

Volume: 18

Electronic Location Identifier: 265

Affiliations

[1 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Department of Neurology, , University Medical Center Hamburg-Eppendorf, ; Martinistraße 52, 20246 Hamburg, Germany

[2 ]GRID grid.10825.3e, ISNI 0000 0001 0728 0170, Department of Neurobiology Research, Institute of Molecular Medicine, , University of Southern Denmark, ; Odense, Denmark

[3 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, I. Medizinische Klinik, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[4 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Institute of Immunology, , Hannover Medical School, ; Hannover, Germany

[5 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Institute of Systems Immunology, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[6 ]GRID grid.47100.32, ISNI 0000000419368710, Department of Immunobiology, The Howard Hughes Medical Institute, , Yale School of Medicine, ; New Haven, CT USA

[7 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Institute of Clinical Chemistry and Laboratory Medicine, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

Article

Publisher ID: 2316

DOI: 10.1186/s12974-021-02316-7

PMC ID: 8590298

PubMed ID: 34772416

SO-VID: 3d8b7033-d696-41b8-b708-5e3ff369845d

License:

Open AccessThis 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.

History

Date received : 29 June 2021

Date accepted : 2 November 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001659, deutsche forschungsgemeinschaft;

Award ID: 428778375

Award Recipient : Mathias Gelderblom

Funded by: Universitätsklinikum Hamburg-Eppendorf (UKE) (5411)

Open Access :

Open Access funding enabled and organized by Projekt DEAL.

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: stroke,ischemia,inflammation,t cells,interleukin-10,interleukin-17

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: stroke, ischemia, inflammation, t cells, interleukin-10, interleukin-17

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

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

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Stroke MRI

Most cited references 39

Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival.

The immunology of stroke: from mechanisms to translation

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