Caspase blockade induces RIP3-mediated programmed necrosis in Toll-like receptor-activated microglia.
Caspase blockade induces RIP3-mediated programmed necrosis in Toll-like receptor-activated microglia.
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DOI：
10.1038/cddis.2013.238
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发表时间：
2013-07-11
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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小胶质细胞是中枢神经系统的常驻免疫细胞，是抵抗病原体和损伤的关键细胞。然而，持续的小胶质细胞激活通常会加剧病理性损伤，并与许多神经系统疾病有关。尽管它们具有关键的生理和病理生理作用，但活化小胶质细胞的生存和死亡是如何被调节的仍然知之甚少。我们在这里报道，当暴露于泛caspase抑制剂zVAD-fmk时，通过toll样受体（TLRs）激活的小胶质细胞发生RIP1/ rip3依赖性程序性坏死（necroptosis）。虽然zad -fmk和caspase-8抑制剂IETD-fmk对未受刺激的原代小胶质细胞没有影响，但它们明显使小胶质细胞对TLR1/2、3,4,7/8配体或TNF治疗敏感，触发程序性坏死，R1P1激酶抑制剂坏死他汀-1完全阻断。有趣的是，TLR配体和zVAD诱导的坏死凋亡仅限于小胶质细胞，而在星形胶质细胞、神经元或少突胶质细胞中未观察到，尽管已知它们表达某些TLR。编码TNF或TNFR1的基因缺失无法阻止脂多糖和聚（I:C）诱导的小胶质细胞坏死，揭示了TLR3-和tlr4激活的小胶质细胞中TNF独立的程序性坏死途径。缺乏功能性TRIF的小鼠的小胶质细胞完全免受TLR3/4激活和zvad -fmk诱导的坏死，rip3的遗传缺失也可以防止小胶质细胞坏死。c-jun n末端激酶的激活和特定活性氧的产生是小胶质细胞死亡执行所需的下游信号事件。综上所述，本研究揭示了在caspase阻断后，TLR激活的小胶质细胞中存在一个强大的rip3依赖性坏死坏死信号通路，并表明TLR信号通路和程序性细胞死亡通路在小胶质细胞中密切相关，当TLR信号通路失调时，可能导致神经病理和神经炎症。
Microglia are the resident immune cells in the central nervous system and key players against pathogens and injury. However, persistent microglial activation often exacerbates pathological damage and has been implicated in many neurological diseases. Despite their pivotal physiological and pathophysiological roles, how the survival and death of activated microglia is regulated remains poorly understood. We report here that microglia activated through Toll-like receptors (TLRs) undergo RIP1/RIP3-dependent programmed necrosis (necroptosis) when exposed to the pan caspase inhibitor zVAD-fmk. Although zVAD-fmk and the caspase-8 inhibitor IETD-fmk had no effect on unstimulated primary microglia, they markedly sensitized microglia to TLR1/2,3,4,7/8 ligands or TNF treatment, triggering programmed necrosis that was completely blocked by R1P1 kinase inhibitor necrostatin-1. Interestingly, necroptosis induced by TLR ligands and zVAD was restricted to microglial cells and was not observed in astrocytes, neurons or oligodendrocytes even though they are known to express certain TLRs. Deletion of genes encoding TNF or TNFR1 failed to prevent lipopolysaccharide- and poly(I:C)-induced microglial necroptosis, unveiling a TNF-independent programmed necrosis pathway in TLR3- and TLR4-activated microglia. Microglia from mice lacking functional TRIF were fully protected against TLR3/4 activation and zVAD-fmk-induced necrosis, and genetic deletion of rip3 also prevented microglia necroptosis. Activation of c-jun N-terminal kinase and generation of specific reactive oxygen species were downstream signaling events required for microglial cell death execution. Taken together, this study reveals a robust RIP3-dependent necroptosis signaling pathway in TLR-activated microglia upon caspase blockade and suggests that TLR signaling and programmed cell death pathways are closely linked in microglia, which could contribute to neuropathology and neuroinflammation when dysregulated.
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