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 language | English |
|---|---|
| Article number | e121560 |
| Number of pages | 16 |
| Journal | JCI Insight |
| Volume | 3 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - 20 Sep 2018 |
Keywords
- Cardiology
- Immunotherapy
- Inflammation
- Mouse models
- Stroke
Cite this
}
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 journal › Article › Research › peer-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
UR - http://www.scopus.com/inward/record.url?scp=85062250394&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.121560
DO - 10.1172/jci.insight.121560
M3 - Article
VL - 3
JO - JCI Insight
JF - JCI Insight
SN - 2379-3708
IS - 18
M1 - e121560
ER -