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

Clausen, Bettina Hjelm; Degn, Matilda; Martin, Nellie Anne; Couch, Yvonne; Karimi, Leena; Ormhoj, Maria; Mortensen, Maria-Louise Bergholdt; Gredal, Hanne Birgit; Gardiner, Chris and Sargent, Ian I. L., et al. (2014) In Journal of Neuroinflammation 11.
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... (More)
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. (Less)
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keywords
SolTNF and tmTNF, Granulocytes, Behavior, Acute phase response, Microvesicle, Inflammation
in
Journal of Neuroinflammation
volume
11
publisher
BioMed Central
external identifiers
  • wos:000347426400001
  • scopus:84924902223
ISSN
1742-2094
DOI
10.1186/s12974-014-0203-6
language
English
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yes
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a4a7df56-ae20-4157-9f1d-3c4a4803312b (old id 5085324)
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2015-03-02 07:12:36
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2017-11-05 03:56:32
@article{a4a7df56-ae20-4157-9f1d-3c4a4803312b,
  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.},
  articleno    = {203},
  author       = {Clausen, Bettina Hjelm and Degn, Matilda and Martin, Nellie Anne and Couch, Yvonne and Karimi, Leena and Ormhoj, Maria and Mortensen, Maria-Louise Bergholdt and Gredal, Hanne Birgit and Gardiner, Chris and Sargent, Ian I. L. and Szymkowski, David E. and Petit, Géraldine and Deierborg, Tomas and Finsen, Bente and Anthony, Daniel Clive and Lambertsen, Kate Lykke},
  issn         = {1742-2094},
  keyword      = {SolTNF and tmTNF,Granulocytes,Behavior,Acute phase response,Microvesicle,Inflammation},
  language     = {eng},
  publisher    = {BioMed Central},
  series       = {Journal of Neuroinflammation},
  title        = {Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia},
  url          = {http://dx.doi.org/10.1186/s12974-014-0203-6},
  volume       = {11},
  year         = {2014},
}