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

Journal of Neuroinflammation

Kate Lykke Lambertsen⁴  Daniel Clive Anthony²  Bente Finsen⁴  Tomas Deierborg⁵  Géraldine H Petit⁵  David E Szymkowski¹  Ian I L Sargent⁷  Chris Gardiner⁷  Hanne Birgit Gredal⁶  Maria-Louise Bergholdt Mortensen⁴  Maria Ormhøj⁴  Leena Karimi⁴  Yvonne Couch²  Nellie Anne Martin⁴  Matilda Degn³  Bettina Hjelm Clausen⁴ 

[1] Xencor Inc, 111 W Lemon Ave, Monrovia 91016, CA, USA;Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK;Department of Diagnostics, Molecular Sleep Laboratory, Glostrup Hospital, Nordre Ringvej 69, Glostrup, 2600, Denmark;Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., Odense, 5000, Denmark;Department of Clinical Sciences, Laboratory for Experimental Medical Science, Neuronal Survival Unit, 22100 Lund University, BMC B11, Sölveg 19, Lund, Sweden;Department of Veterinary Clinical and Animal Sciences, Facuty of Health and Medical Sciences, University of Copenhagen, Dyrlægevej 16, Frederiksberg, 1870, Denmark;Nuffield Department of Obstetrics and Gynecology, University of Oxford, Headley Way, Oxford, OX1 3QT, UK

关键词: Inflammation;    Microvesicle;    Acute phase response;    Behavior;    Granulocytes;    SolTNF and tmTNF;   

Others  :  1149920
DOI  :  10.1186/s12974-014-0203-6

 received in 2014-07-04, accepted in 2014-11-15,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Clausen et al.; licensee BioMed Central Ltd.

【 图 表 】

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