Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration
Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration
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DOI：
10.1073/pnas.1605195113
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发表时间：
2016-10-25
影响因子：
11.1
通讯作者：
Eisel, Ulrich L. M.
中科院分区：
文献类型：
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作者：
Dong, Yun;Fischer, Roman;Eisel, Ulrich L. M.
尽管肿瘤坏死因子（TNF）在炎症和神经元变性中的作用已得到公认，但抗TNF治疗未能治疗神经退行性疾病。动物疾病模型揭示了两种TNF受体（TNFR）在中枢神经系统中的拮抗作用，其中TNFR1与炎症变性有关，TNFR2与神经保护有关。我们在此展示了在nmda诱导的急性神经变性小鼠模型中，ATROSAB（一种TNFR1选择性拮抗抗体）和EHD2-scTNF(R2)（一种TNFR2选择性激动性TNF）分别选择性抑制TNFR1和激活TNFR2的治疗潜力。将ATROSAB或EHD2-scTNF（R2）共同注入大细胞核基底核，可显著保护胆碱能神经元及其皮层突起免受细胞死亡，并以被动回避模式恢复神经退行性相关的记忆障碍。然而，同时阻断TNFR1和TNFR2信号通路会使治疗效果失效。我们的研究结果揭示了TNFR2在神经保护中的重要作用。因此，ATROSAB的治疗活性是通过将内源性TNF的拮抗活性平衡向TNFR2转移而介导的，TNFR2似乎对神经保护至关重要。我们的数据还解释了早期的结果，表明抗TNF药物完全阻断TNF活性是有害的，而不是保护的，并主张使用下一代tnfr选择性TNF疗法作为治疗神经退行性疾病的有效方法。
Despite the recognized role of tumor necrosis factor (TNF) in inflammation and neuronal degeneration, anti-TNF therapeutics failed to treat neurodegenerative diseases. Animal disease models had revealed the antithetic effects of the two TNF receptors (TNFR) in the central nervous system, whereby TNFR1 has been associated with inflammatory degeneration and TNFR2 with neuroprotection. We here show the therapeutic potential of selective inhibition of TNFR1 and activation of TNFR2 by ATROSAB, a TNFR1-selective antagonistic antibody, and EHD2-scTNF(R2), an agonistic TNFR2-selective TNF, respectively, in a mouse model of NMDA-induced acute neurodegeneration. Coadministration of either ATROSAB or EHD2-scTNF(R2) into the magnocellular nucleus basalis significantly protected cholinergic neurons and their cortical projections against cell death, and reverted the neurodegeneration-associated memory impairment in a passive avoidance paradigm. Simultaneous blocking of TNFR1 and TNFR2 signaling, however, abrogated the therapeutic effect. Our results uncover an essential role of TNFR2 in neuroprotection. Accordingly, the therapeutic activity of ATROSAB is mediated by shifting the balance of the antithetic activity of endogenous TNF toward TNFR2, which appears essential for neuroprotection. Our data also explain earlier results showing that complete blocking of TNF activity by anti-TNF drugs was detrimental rather than protective and argue for the use of next-generation TNFR-selective TNF therapeutics as an effective approach in treating neurodegenerative diseases.