IL-33 modulates inflammatory brain injury but exacerbates systemic immunosuppression following ischemic stroke

Shenpeng R. Zhang, Marius Piepke, Hannah X. Chu, Brad R.S. Broughton, Raymond Shim, Connie H.Y. Wong, Seyoung Lee, Megan A. Evans, Antony Vinh, Samy Sakkal, Thiruma V. Arumugam, Tim Magnus, Samuel Huber, Mathias Gelderblom, Grant R. Drummond, Christopher G. Sobey, Hyun Ah Kim

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Stroke triggers a complex inflammatory process in which the balance between pro- and antiinflammatory mediators is critical for the development of the brain infarct. However, systemic changes may also occur in parallel with brain inflammation. Here we demonstrate that administration of recombinant IL-33, a recently described member of the IL-1 superfamily of cytokines, promotes Th2-type effects following focal ischemic stroke, resulting in increased plasma levels of Th2-type cytokines and fewer proinflammatory (3-nitrotyrosine+F4/80+) microglia/macrophages in the brain. These effects of IL-33 were associated with reduced infarct size, fewer activated microglia and infiltrating cytotoxic (natural killer-like) T cells, and more IL-10-expressing regulatory T cells. Despite these neuroprotective effects, mice treated with IL-33 displayed exacerbated post-stroke lung bacterial infection in association with greater functional deficits and mortality at 24 hours. Supplementary antibiotics (gentamicin and ampicillin) mitigated these systemic effects of IL-33 after stroke. Our findings highlight the complex nature of the inflammatory mechanisms differentially activated in the brain and periphery during the acute phase after ischemic stroke. The data indicate that a Th2-promoting agent can provide neuroprotection without adverse systemic effects when given in combination with antibiotics.

Original languageEnglish
Article numbere121560
Number of pages16
JournalJCI Insight
Volume3
Issue number18
DOIs
Publication statusPublished - 20 Sep 2018

Keywords

  • Cardiology
  • Immunotherapy
  • Inflammation
  • Mouse models
  • Stroke

Cite this

Zhang, Shenpeng R. ; Piepke, Marius ; Chu, Hannah X. ; Broughton, Brad R.S. ; Shim, Raymond ; Wong, Connie H.Y. ; Lee, Seyoung ; Evans, Megan A. ; Vinh, Antony ; Sakkal, Samy ; Arumugam, Thiruma V. ; Magnus, Tim ; Huber, Samuel ; Gelderblom, Mathias ; Drummond, Grant R. ; Sobey, Christopher G. ; Kim, Hyun Ah. / IL-33 modulates inflammatory brain injury but exacerbates systemic immunosuppression following ischemic stroke. In: JCI Insight. 2018 ; Vol. 3, No. 18.
@article{c1862b3d45674044b35cf516effb3905,
title = "IL-33 modulates inflammatory brain injury but exacerbates systemic immunosuppression following ischemic stroke",
abstract = "Stroke triggers a complex inflammatory process in which the balance between pro- and antiinflammatory mediators is critical for the development of the brain infarct. However, systemic changes may also occur in parallel with brain inflammation. Here we demonstrate that administration of recombinant IL-33, a recently described member of the IL-1 superfamily of cytokines, promotes Th2-type effects following focal ischemic stroke, resulting in increased plasma levels of Th2-type cytokines and fewer proinflammatory (3-nitrotyrosine+F4/80+) microglia/macrophages in the brain. These effects of IL-33 were associated with reduced infarct size, fewer activated microglia and infiltrating cytotoxic (natural killer-like) T cells, and more IL-10-expressing regulatory T cells. Despite these neuroprotective effects, mice treated with IL-33 displayed exacerbated post-stroke lung bacterial infection in association with greater functional deficits and mortality at 24 hours. Supplementary antibiotics (gentamicin and ampicillin) mitigated these systemic effects of IL-33 after stroke. Our findings highlight the complex nature of the inflammatory mechanisms differentially activated in the brain and periphery during the acute phase after ischemic stroke. The data indicate that a Th2-promoting agent can provide neuroprotection without adverse systemic effects when given in combination with antibiotics.",
keywords = "Cardiology, Immunotherapy, Inflammation, Mouse models, Stroke",
author = "Zhang, {Shenpeng R.} and Marius Piepke and Chu, {Hannah X.} and Broughton, {Brad R.S.} and Raymond Shim and Wong, {Connie H.Y.} and Seyoung Lee and Evans, {Megan A.} and Antony Vinh and Samy Sakkal and Arumugam, {Thiruma V.} and Tim Magnus and Samuel Huber and Mathias Gelderblom and Drummond, {Grant R.} and Sobey, {Christopher G.} and Kim, {Hyun Ah}",
year = "2018",
month = "9",
day = "20",
doi = "10.1172/jci.insight.121560",
language = "English",
volume = "3",
journal = "JCI Insight",
issn = "2379-3708",
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Zhang, SR, Piepke, M, Chu, HX, Broughton, BRS, Shim, R, Wong, CHY, Lee, S, Evans, MA, Vinh, A, Sakkal, S, Arumugam, TV, Magnus, T, Huber, S, Gelderblom, M, Drummond, GR, Sobey, CG & Kim, HA 2018, 'IL-33 modulates inflammatory brain injury but exacerbates systemic immunosuppression following ischemic stroke', JCI Insight, vol. 3, no. 18, e121560. https://doi.org/10.1172/jci.insight.121560

IL-33 modulates inflammatory brain injury but exacerbates systemic immunosuppression following ischemic stroke. / Zhang, Shenpeng R.; Piepke, Marius; Chu, Hannah X.; Broughton, Brad R.S.; Shim, Raymond; Wong, Connie H.Y.; Lee, Seyoung; Evans, Megan A.; Vinh, Antony; Sakkal, Samy; Arumugam, Thiruma V.; Magnus, Tim; Huber, Samuel; Gelderblom, Mathias; Drummond, Grant R.; Sobey, Christopher G.; Kim, Hyun Ah.

In: JCI Insight, Vol. 3, No. 18, e121560, 20.09.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - IL-33 modulates inflammatory brain injury but exacerbates systemic immunosuppression following ischemic stroke

AU - Zhang, Shenpeng R.

AU - Piepke, Marius

AU - Chu, Hannah X.

AU - Broughton, Brad R.S.

AU - Shim, Raymond

AU - Wong, Connie H.Y.

AU - Lee, Seyoung

AU - Evans, Megan A.

AU - Vinh, Antony

AU - Sakkal, Samy

AU - Arumugam, Thiruma V.

AU - Magnus, Tim

AU - Huber, Samuel

AU - Gelderblom, Mathias

AU - Drummond, Grant R.

AU - Sobey, Christopher G.

AU - Kim, Hyun Ah

PY - 2018/9/20

Y1 - 2018/9/20

N2 - Stroke triggers a complex inflammatory process in which the balance between pro- and antiinflammatory mediators is critical for the development of the brain infarct. However, systemic changes may also occur in parallel with brain inflammation. Here we demonstrate that administration of recombinant IL-33, a recently described member of the IL-1 superfamily of cytokines, promotes Th2-type effects following focal ischemic stroke, resulting in increased plasma levels of Th2-type cytokines and fewer proinflammatory (3-nitrotyrosine+F4/80+) microglia/macrophages in the brain. These effects of IL-33 were associated with reduced infarct size, fewer activated microglia and infiltrating cytotoxic (natural killer-like) T cells, and more IL-10-expressing regulatory T cells. Despite these neuroprotective effects, mice treated with IL-33 displayed exacerbated post-stroke lung bacterial infection in association with greater functional deficits and mortality at 24 hours. Supplementary antibiotics (gentamicin and ampicillin) mitigated these systemic effects of IL-33 after stroke. Our findings highlight the complex nature of the inflammatory mechanisms differentially activated in the brain and periphery during the acute phase after ischemic stroke. The data indicate that a Th2-promoting agent can provide neuroprotection without adverse systemic effects when given in combination with antibiotics.

AB - Stroke triggers a complex inflammatory process in which the balance between pro- and antiinflammatory mediators is critical for the development of the brain infarct. However, systemic changes may also occur in parallel with brain inflammation. Here we demonstrate that administration of recombinant IL-33, a recently described member of the IL-1 superfamily of cytokines, promotes Th2-type effects following focal ischemic stroke, resulting in increased plasma levels of Th2-type cytokines and fewer proinflammatory (3-nitrotyrosine+F4/80+) microglia/macrophages in the brain. These effects of IL-33 were associated with reduced infarct size, fewer activated microglia and infiltrating cytotoxic (natural killer-like) T cells, and more IL-10-expressing regulatory T cells. Despite these neuroprotective effects, mice treated with IL-33 displayed exacerbated post-stroke lung bacterial infection in association with greater functional deficits and mortality at 24 hours. Supplementary antibiotics (gentamicin and ampicillin) mitigated these systemic effects of IL-33 after stroke. Our findings highlight the complex nature of the inflammatory mechanisms differentially activated in the brain and periphery during the acute phase after ischemic stroke. The data indicate that a Th2-promoting agent can provide neuroprotection without adverse systemic effects when given in combination with antibiotics.

KW - Cardiology

KW - Immunotherapy

KW - Inflammation

KW - Mouse models

KW - Stroke

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