Necrostatin-1 enhances the resolution of inflammation by specifically inducing neutrophil apoptosis
Necrostatin-1 enhances the resolution of inflammation by specifically inducing neutrophil apoptosis
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Necrostatin-1 通过特异性诱导中性粒细胞凋亡来增强炎症的消退
DOI：
10.18632/oncotarget.8346
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发表时间：
2016-04-12
期刊：
影响因子：
--
通讯作者：
Sun, Erwei
中科院分区：
文献类型：
--
作者：
Jie, Hongyu;He, Yi;Sun, Erwei
中性粒细胞在先天免疫中起着核心作用，并迅速被招募到感染和损伤部位。神经细胞凋亡对于炎症的成功消退是必不可少的。Necrostatin-1（Nec-1，甲基-硫代乙内酰脲-色氨酸（MTH-Trp））是一种通过抑制受体相互作用蛋白1（RIP 1）激酶来抑制坏死性凋亡（一种新发现的细胞死亡类型，代表一种程序性坏死或受调节的非凋亡性细胞死亡）的强效特异性抑制剂[1]。在这里，我们报告说，Nec-1特异性诱导半胱天冬酶依赖的中性粒细胞凋亡，并推翻强大的抗凋亡信号从生存因子，如GM-CSF和LPS。我们发现，Nec-1显著增强了LPS诱导的小鼠急性肺损伤中已建立的嗜中性粒细胞依赖性炎症的消退。我们还提供了证据表明，Nec-1通过减少抗凋亡蛋白Mcl-1的表达和增加促凋亡蛋白Bax的表达来促进凋亡。因此，Nec-1不仅是坏死性凋亡的抑制剂，而且是中性粒细胞凋亡的促进剂，通过诱导炎性细胞凋亡来增强已建立的炎症的消退。我们的研究结果表明，Nec-1可能具有治疗炎症反应增加或持续性疾病的潜在作用。
Neutrophils play a central role in innate immunity and are rapidly recruited to sites of infection and injury. Neutrophil apoptosis is essential for the successful resolution of inflammation. Necrostatin-1 (Nec-1,methyl-thiohydantoin-tryptophan (MTH-Trp)), is a potent and specific inhibitor of necroptosis[1] (a newly identified type of cell death representing a form of programmed necrosis or regulated non apoptotic cell death) by inhibiting the receptor interacting protein 1(RIP1) kinase. Here we report that Nec-1 specifically induces caspase-dependent neutrophils apoptosis and overrides powerful anti-apoptosis signaling from survival factors such as GM-CSF and LPS. We showed that Nec-1 markedly enhanced the resolution of established neutrophil-dependent inflammation in LPS-induced acute lung injury in mice. We also provided evidence that Nec-1 promoted apoptosis by reducing the expression of the anti-apoptotic protein Mcl-1 and increasing the expression of pro-apoptotic protein Bax. Thus, Nec-1 is not only an inhibitor of necroptosis, but also a promoter of apoptosis, of neutrophils, enhancing the resolution of established inflammation by inducing apoptosis of inflammatory cells. Our results suggest that Nec-1 may have potential roles for the treatment of diseases with increased or persistent inflammatory responses.