Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia

Bettina Hjelm Clausen; Matilda Degn; Nellie Anne Martin; Yvonne Couch; Leena Karimi; Maria Ormhøj; Maria-Louise Bergholdt Mortensen; Hanne Birgit Gredal; Chris Gardiner; Ian I. L. Sargent; David E. Szymkowski; Geraldine H. Petit; Tomas Deierborg; Bente Finsen; Daniel Clive Anthony; Kate Lykke Lambertsen

doi:10.1186/s12974-014-0203-6

Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia

Bettina Hjelm Clausen, Matilda Degn, Nellie Anne Martin, Yvonne Couch, Leena Karimi, Maria Ormhøj, Maria-Louise Bergholdt Mortensen, Hanne Birgit Gredal, Chris Gardiner, Ian I. L. Sargent, David E. Szymkowski, Geraldine H. Petit, Tomas Deierborg, Bente Finsen, Daniel Clive Anthony, Kate Lykke Lambertsen

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Abstract

Background: The innate immune system contributes to the outcome after stroke, where neuroinflammation and post-stroke systemic immune depression are central features. Tumor necrosis factor (TNF), which exists in both a transmembrane (tm) and soluble (sol) form, is known to sustain complex inflammatory responses associated with stroke. We tested the effect of systemically blocking only solTNF versus blocking both tmTNF and solTNF on infarct volume, functional outcome and inflammation in focal cerebral ischemia. Methods: We used XPro1595 (a dominant-negative inhibitor of solTNF) and etanercept (which blocks both solTNF and tmTNF) to test the effect of systemic administration on infarct volume, functional recovery and inflammation after focal cerebral ischemia in mice. Functional recovery was evaluated after one, three and five days, and infarct volumes at six hours, 24 hours and five days after ischemia. Brain inflammation, liver acute phase response (APR), spleen and blood leukocyte profiles, along with plasma microvesicle analysis, were evaluated. Results: We found that both XPro1595 and etanercept significantly improved functional outcomes, altered microglial responses, and modified APR, spleen T cell and microvesicle numbers, but without affecting infarct volumes. Conclusions: Our data suggest that XPro1595 and etanercept improve functional outcome after focal cerebral ischemia by altering the peripheral immune response, changing blood and spleen cell populations and decreasing granulocyte infiltration into the brain. Blocking solTNF, using XPro1595, was just as efficient as blocking both solTNF and tmTNF using etanercept. Our findings may have implications for future treatments with anti-TNF drugs in TNF-dependent diseases.

Original language	English
Article number	203
Journal	Journal of Neuroinflammation
Volume	11
Number of pages	17
ISSN	1742-2094
DOIs	https://doi.org/10.1186/s12974-014-0203-6
Publication status	Published - 12 Dec 2014

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Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemiaFinal published version, 1.61 MB

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Clausen, B. H., Degn, M., Martin, N. A., Couch, Y., Karimi, L., Ormhøj, M., Mortensen, M.-L. B., Gredal, H. B., Gardiner, C., Sargent, I. I. L., Szymkowski, D. E., Petit, G. H., Deierborg, T., Finsen, B., Anthony, D. C., & Lambertsen, K. L. (2014). Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia. Journal of Neuroinflammation, 11, Article 203. https://doi.org/10.1186/s12974-014-0203-6

Clausen, BH, Degn, M, Martin, NA, Couch, Y, Karimi, L, Ormhøj, M, Mortensen, M-LB, Gredal, HB, Gardiner, C, Sargent, IIL, Szymkowski, DE, Petit, GH, Deierborg, T, Finsen, B, Anthony, DC & Lambertsen, KL 2014, 'Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia', Journal of Neuroinflammation, vol. 11, 203. https://doi.org/10.1186/s12974-014-0203-6

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title = "Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia",

abstract = "Background: The innate immune system contributes to the outcome after stroke, where neuroinflammation and post-stroke systemic immune depression are central features. Tumor necrosis factor (TNF), which exists in both a transmembrane (tm) and soluble (sol) form, is known to sustain complex inflammatory responses associated with stroke. We tested the effect of systemically blocking only solTNF versus blocking both tmTNF and solTNF on infarct volume, functional outcome and inflammation in focal cerebral ischemia. Methods: We used XPro1595 (a dominant-negative inhibitor of solTNF) and etanercept (which blocks both solTNF and tmTNF) to test the effect of systemic administration on infarct volume, functional recovery and inflammation after focal cerebral ischemia in mice. Functional recovery was evaluated after one, three and five days, and infarct volumes at six hours, 24 hours and five days after ischemia. Brain inflammation, liver acute phase response (APR), spleen and blood leukocyte profiles, along with plasma microvesicle analysis, were evaluated. Results: We found that both XPro1595 and etanercept significantly improved functional outcomes, altered microglial responses, and modified APR, spleen T cell and microvesicle numbers, but without affecting infarct volumes. Conclusions: Our data suggest that XPro1595 and etanercept improve functional outcome after focal cerebral ischemia by altering the peripheral immune response, changing blood and spleen cell populations and decreasing granulocyte infiltration into the brain. Blocking solTNF, using XPro1595, was just as efficient as blocking both solTNF and tmTNF using etanercept. Our findings may have implications for future treatments with anti-TNF drugs in TNF-dependent diseases.",

author = "Clausen, {Bettina Hjelm} and Matilda Degn and Martin, {Nellie Anne} and Yvonne Couch and Leena Karimi and Maria Ormh{\o}j and Mortensen, {Maria-Louise Bergholdt} and Gredal, {Hanne Birgit} and Chris Gardiner and Sargent, {Ian I. L.} and Szymkowski, {David E.} and Petit, {Geraldine H.} and Tomas Deierborg and Bente Finsen and Anthony, {Daniel Clive} and Lambertsen, {Kate Lykke}",

year = "2014",

month = dec,

day = "12",

doi = "10.1186/s12974-014-0203-6",

language = "English",

volume = "11",

journal = "Journal of Neuroinflammation",

issn = "1742-2094",

publisher = "BioMed Central",

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TY - JOUR

T1 - Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia

AU - Clausen, Bettina Hjelm

AU - Degn, Matilda

AU - Martin, Nellie Anne

AU - Couch, Yvonne

AU - Karimi, Leena

AU - Ormhøj, Maria

AU - Mortensen, Maria-Louise Bergholdt

AU - Gredal, Hanne Birgit

AU - Gardiner, Chris

AU - Sargent, Ian I. L.

AU - Szymkowski, David E.

AU - Petit, Geraldine H.

AU - Deierborg, Tomas

AU - Finsen, Bente

AU - Anthony, Daniel Clive

AU - Lambertsen, Kate Lykke

PY - 2014/12/12

Y1 - 2014/12/12

N2 - Background: The innate immune system contributes to the outcome after stroke, where neuroinflammation and post-stroke systemic immune depression are central features. Tumor necrosis factor (TNF), which exists in both a transmembrane (tm) and soluble (sol) form, is known to sustain complex inflammatory responses associated with stroke. We tested the effect of systemically blocking only solTNF versus blocking both tmTNF and solTNF on infarct volume, functional outcome and inflammation in focal cerebral ischemia. Methods: We used XPro1595 (a dominant-negative inhibitor of solTNF) and etanercept (which blocks both solTNF and tmTNF) to test the effect of systemic administration on infarct volume, functional recovery and inflammation after focal cerebral ischemia in mice. Functional recovery was evaluated after one, three and five days, and infarct volumes at six hours, 24 hours and five days after ischemia. Brain inflammation, liver acute phase response (APR), spleen and blood leukocyte profiles, along with plasma microvesicle analysis, were evaluated. Results: We found that both XPro1595 and etanercept significantly improved functional outcomes, altered microglial responses, and modified APR, spleen T cell and microvesicle numbers, but without affecting infarct volumes. Conclusions: Our data suggest that XPro1595 and etanercept improve functional outcome after focal cerebral ischemia by altering the peripheral immune response, changing blood and spleen cell populations and decreasing granulocyte infiltration into the brain. Blocking solTNF, using XPro1595, was just as efficient as blocking both solTNF and tmTNF using etanercept. Our findings may have implications for future treatments with anti-TNF drugs in TNF-dependent diseases.

AB - Background: The innate immune system contributes to the outcome after stroke, where neuroinflammation and post-stroke systemic immune depression are central features. Tumor necrosis factor (TNF), which exists in both a transmembrane (tm) and soluble (sol) form, is known to sustain complex inflammatory responses associated with stroke. We tested the effect of systemically blocking only solTNF versus blocking both tmTNF and solTNF on infarct volume, functional outcome and inflammation in focal cerebral ischemia. Methods: We used XPro1595 (a dominant-negative inhibitor of solTNF) and etanercept (which blocks both solTNF and tmTNF) to test the effect of systemic administration on infarct volume, functional recovery and inflammation after focal cerebral ischemia in mice. Functional recovery was evaluated after one, three and five days, and infarct volumes at six hours, 24 hours and five days after ischemia. Brain inflammation, liver acute phase response (APR), spleen and blood leukocyte profiles, along with plasma microvesicle analysis, were evaluated. Results: We found that both XPro1595 and etanercept significantly improved functional outcomes, altered microglial responses, and modified APR, spleen T cell and microvesicle numbers, but without affecting infarct volumes. Conclusions: Our data suggest that XPro1595 and etanercept improve functional outcome after focal cerebral ischemia by altering the peripheral immune response, changing blood and spleen cell populations and decreasing granulocyte infiltration into the brain. Blocking solTNF, using XPro1595, was just as efficient as blocking both solTNF and tmTNF using etanercept. Our findings may have implications for future treatments with anti-TNF drugs in TNF-dependent diseases.

U2 - 10.1186/s12974-014-0203-6

DO - 10.1186/s12974-014-0203-6

M3 - Journal article

C2 - 25498129

SN - 1742-2094

VL - 11

JO - Journal of Neuroinflammation

JF - Journal of Neuroinflammation

M1 - 203

ER -

Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia

Abstract

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