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 B Mortensen, Hanne Gredal, Chris Gardiner, Ian I.L. Sargent, David E Szymkowski, Geraldine Petit, Tomas Deierborg, Bente Finsen, Daniel Anthony, Kate Lykke Lambertsen

Research output: Contribution to journalJournal articleResearchpeer-review

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 languageEnglish
Article number203
JournalJournal of Neuroinflammation
Volume11
Issue number1
Number of pages17
ISSN1742-2094
DOIs
Publication statusPublished - 12. Dec 2014

Keywords

  • Acute phase response
  • Behavior
  • Granulocytes
  • Inflammation
  • Microvesicle
  • SolTNF and tmTNF
  • Brain Ischemia/drug therapy
  • Injections, Intravenous
  • Mice, Inbred C57BL
  • Male
  • Treatment Outcome
  • Random Allocation
  • Recovery of Function/drug effects
  • Tumor Necrosis Factor-alpha/administration & dosage
  • Animals
  • Mice

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