Clausen Bettina Hjelm, Degn Matilda, Martin Nellie Anne, Couch Yvonne, Karimi Leena, Ormhøj Maria, Mortensen Maria-Louise Bergholdt, Gredal Hanne Birgit, Gardiner Chris, Sargent Ian I L, Szymkowski David E, Petit Géraldine H, Deierborg Tomas, Finsen Bente, Anthony Daniel Clive, Lambertsen Kate Lykke
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark.
Department of Diagnostics, Molecular Sleep Laboratory, Glostrup Hospital, Nordre Ringvej 69, 2600, Glostrup, Denmark.
J Neuroinflammation. 2014 Dec 12;11:203. doi: 10.1186/s12974-014-0203-6.
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.
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.
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.
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.
先天性免疫系统对中风后的预后有影响，其中神经炎症和中风后全身免疫抑制是主要特征。肿瘤坏死因子（TNF）以跨膜（tm）和可溶性（sol）两种形式存在，已知其能维持与中风相关的复杂炎症反应。我们测试了仅系统性阻断可溶性TNF（solTNF）与同时阻断跨膜TNF（tmTNF）和可溶性TNF对局灶性脑缺血梗死体积、功能结局和炎症的影响。
我们使用XPro1595（一种可溶性TNF的显性负性抑制剂）和依那西普（可同时阻断可溶性TNF和跨膜TNF）来测试系统性给药对局灶性脑缺血小鼠梗死体积、功能恢复和炎症的影响。在第1、3和5天评估功能恢复情况，在缺血后6小时、24小时和5天评估梗死体积。评估脑炎症、肝脏急性期反应（APR）、脾脏和血液白细胞谱以及血浆微泡分析。
我们发现XPro1595和依那西普均显著改善了功能结局，改变了小胶质细胞反应，并改变了急性期反应、脾脏T细胞和微泡数量，但不影响梗死体积。
我们的数据表明，XPro1595和依那西普通过改变外周免疫反应、改变血液和脾脏细胞群以及减少粒细胞向脑内浸润，改善了局灶性脑缺血后的功能结局。使用XPro1595阻断可溶性TNF与使用依那西普同时阻断可溶性TNF和跨膜TNF一样有效。我们的发现可能对未来TNF依赖性疾病的抗TNF药物治疗有启示意义。
