Role for RIP1 in mediating necroptosis in experimental intracerebral hemorrhage model both in vivo and in vitro.
Role for RIP1 in mediating necroptosis in experimental intracerebral hemorrhage model both in vivo and in vitro.
复制标题
RIP1 在体内和体外实验性脑出血模型中介导坏死性凋亡中的作用
DOI：
10.1038/cddis.2017.58
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发表时间：
2017-03-02
影响因子：
9
通讯作者：
Chen G
中科院分区：
文献类型：
--
作者：
Shen H;Liu C;Zhang D;Yao X;Zhang K;Li H;Chen G
细胞死亡是脑出血后继发性脑损伤的标志，其机制尚未完全阐明。在这项研究中，我们探讨了坏死性凋亡，一种调节性坏死，是否在脑出血后的脑损伤中起重要作用。我们发现，抑制受体相互作用蛋白1（RIP 1）-坏死性凋亡途径的核心要素-通过特定的化学抑制剂或基因敲减减轻脑出血大鼠模型的脑损伤。此外，经氧血红蛋白刺激的小胶质细胞条件培养液可诱导培养神经元坏死性凋亡，这种作用可被TNF-α抑制剂抑制，表明激活的小胶质细胞分泌的TNF-α是诱导神经元坏死性凋亡的重要因素。RIP 1的过度表达无疑增强了条件培养基诱导的体外坏死性凋亡，但RIP 1丝氨酸激酶磷酸化位点的突变部分减弱了这种作用，表明RIP 1的磷酸化是脑出血体外模型中激活的坏死性凋亡的重要分子机制。总之，我们的研究表明，坏死性凋亡是脑出血后脑损伤细胞死亡的重要机制，抑制坏死性凋亡可能是脑出血的潜在治疗干预措施。
Cell death is a hallmark of second brain injury after intracerebral hemorrhage (ICH); however, the mechanism still has not been fully illustrated. In this study, we explored whether necroptosis, a type of regulated necrosis, has an essential role in brain injury after ICH. We found that inhibiting receptor-interacting protein 1 (RIP1)–a core element of the necroptotic pathway–by a specific chemical inhibitor or genetic knockdown attenuated brain injury in a rat model of ICH. Furthermore, necroptosis of cultured neurons could be induced by conditioned medium from microglia stimulated with oxygen hemoglobin, and this effect could be inhibited by TNF-α inhibitor, indicating that TNF-α secreted from activated microglia is an important factor in inducing necroptosis of neurons. Undoubtedly, overexpression of RIP1 increased conditioned medium-induced necroptosis in vitro, but this effect was partially diminished in mutation of serine kinase phosphorylation site of RIP1, showing that phosphorylation of RIP1 is the essential molecular mechanism of necroptosis, which was activated in the in vitro model of ICH. Collectively, our investigation identified that necroptosis is an important mechanism of cell death in brain injury after ICH, and inhibition of necroptosis may be a potential therapeutic intervention of ICH.