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

J Neuroinflammation. 2021 Nov 13;18(1):265. doi: 10.1186/s12974-021-02316-7.

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.

Keywords: Inflammation; Interleukin-10; Interleukin-17; Ischemia; Stroke; T cells.

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • Immunohistochemistry
  • Infarction, Middle Cerebral Artery / prevention & control
  • Injections, Spinal
  • Interleukin-10 / administration & dosage
  • Interleukin-10 / therapeutic use*
  • Interleukin-17 / antagonists & inhibitors*
  • Ischemic Stroke / drug therapy*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Interleukin-10 / antagonists & inhibitors
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • Treatment Outcome

Substances

  • Antibodies, Neutralizing
  • IL10 protein, mouse
  • Interleukin-17
  • Receptors, Interleukin-10
  • Interleukin-10