NLRP3-dependent pyroptosis is required for HIV-1 gp120-induced neuropathology
NLRP3-dependent pyroptosis is required for HIV-1 gp120-induced neuropathology
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DOI：
10.1038/s41423-019-0260-y
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发表时间：
2020-03-01
影响因子：
24.1
通讯作者：
Cao, Hong
中科院分区：
文献类型：
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作者：
He, Xiaolong;Yang, Weijun;Cao, Hong
人类免疫缺陷病毒-1（HIV-1）包膜蛋白gp 120是HIV相关神经认知障碍（HAND）发病机制的主要贡献者。神经炎症在gp 120诱导的神经病理学中起着关键作用，但gp 120如何触发神经炎症过程和随后的神经元死亡仍不清楚。在这里，我们提供的证据表明，NLRP 3是必需的gp 120诱导的神经炎症和神经病变。我们的研究结果表明，gp 120诱导小胶质细胞中NLRP 3依赖的焦亡和IL-1 β的产生。抑制小胶质细胞NLRP 3炎性小体活化可减轻gp 120介导的神经炎性因子释放和神经元损伤。重要的是，我们发现，长期给予MCC 950，一种新的选择性NLRP 3抑制剂，gp 120转基因小鼠不仅减轻神经炎症和神经元死亡，而且促进神经元再生和恢复受损的神经认知功能。总之，我们的数据显示，NLRP 3炎性小体是重要的gp 120诱导的神经炎症和神经病理学，并建议NLRP 3是一个潜在的新的目标，用于治疗手。
The human immunodeficiency virus-1 (HIV-1) envelope protein gp120 is the major contributor to the pathogenesis of HIV-associated neurocognitive disorder (HAND). Neuroinflammation plays a pivotal role in gp120-induced neuropathology, but how gp120 triggers neuroinflammatory processes and subsequent neuronal death remains unknown. Here, we provide evidence that NLRP3 is required for gp120-induced neuroinflammation and neuropathy. Our results showed that gp120-induced NLRP3-dependent pyroptosis and IL-1 beta production in microglia. Inhibition of microglial NLRP3 inflammasome activation alleviated gp120-mediated neuroinflammatory factor release and neuronal injury. Importantly, we showed that chronic administration of MCC950, a novel selective NLRP3 inhibitor, to gp120 transgenic mice not only attenuated neuroinflammation and neuronal death but also promoted neuronal regeneration and restored the impaired neurocognitive function. In conclusion, our data revealed that the NLRP3 inflammasome is important for gp120-induced neuroinflammation and neuropathology and suggest that NLRP3 is a potential novel target for the treatment of HAND.