Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia.
Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia.
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DOI：
10.1186/s12974-014-0203-6
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发表时间：
2014-12-12
影响因子：
9.3
通讯作者：
Lambertsen KL
中科院分区：
文献类型：
--
作者：
Clausen BH;Degn M;Martin NA;Couch Y;Karimi L;Ormhøj M;Mortensen ML;Gredal HB;Gardiner C;Sargent II;Szymkowski DE;Petit GH;Deierborg T;Finsen B;Anthony DC;Lambertsen KL
先天免疫系统对中风后的结果有贡献，其中神经炎症和中风后全身免疫抑制是中心特征。肿瘤坏死因子（TNF）以跨膜（tm）和可溶性（sol）形式存在，已知其维持与中风相关的复杂炎症反应。我们测试了仅全身阻断solTNF与阻断tmTNF和solTNF两者对局灶性脑缺血中的梗死体积、功能结果和炎症的影响。我们使用XPro 1595（solTNF的显性负性抑制剂）和依那西普（其阻断solTNF和tmTNF）来测试全身给药对小鼠局灶性脑缺血后的梗死体积、功能恢复和炎症的影响。在缺血后1天、3天和5天评价功能恢复，并在缺血后6小时、24小时和5天评价梗死体积。评价了脑炎症、肝脏急性期反应（APR）、脾脏和血液白细胞谱沿着血浆微泡分析。我们发现XPro 1595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APR、脾T细胞和微泡数量，但不影响梗死体积。我们的数据表明，XPro 1595和依那西普改善功能结果后，局灶性脑缺血改变外周免疫反应，改变血液和脾细胞群，减少粒细胞浸润到大脑。使用XPro 1595阻断solTNF与使用依那西普阻断solTNF和tmTNF一样有效。我们的研究结果可能对未来TNF依赖性疾病的抗TNF药物治疗有影响。本文的在线版本（doi：10.1186/s12974-014-0203-6）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1186/s12974-014-0203-6) contains supplementary material, which is available to authorized users.
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影响因子：
9.3
作者：
Novrup HG;Bracchi-Ricard V;Ellman DG;Ricard J;Jain A;Runko E;Lyck L;Yli-Karjanmaa M;Szymkowski DE;Pearse DD;Lambertsen KL;Bethea JR
通讯作者：
Bethea JR
影响因子：
14.5
作者：
Brambilla, Roberta;Ashbaugh, Jessica Jopek;Bethea, John R.
通讯作者：
Bethea, John R.
影响因子：
4.7
作者：
Chio, Chung-Ching;Lin, Jia-Wei;Chang, Ching-Ping
通讯作者：
Chang, Ching-Ping
DOI：
10.3233/jpd-140410
发表时间：
2014
期刊：
Journal of Parkinson's disease
影响因子：
--
作者：
Barnum CJ;Chen X;Chung J;Chang J;Williams M;Grigoryan N;Tesi RJ;Tansey MG
通讯作者：
Tansey MG
影响因子：
2.7
作者：
Bautista, LE;Vera, LM;Gamarra, G
通讯作者：
Gamarra, G