Abstract
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-1β 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.
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Acknowledgements
This project was financially supported by the Key Program of the Natural Science Foundation of Guangdong, China (No. 2017B030311017), the National Natural Science Foundation of China (No. 81370740), the Program of the Natural Science Foundation of Guangdong, China (No. 2018A030313845), and the China Postdoctoral Science Foundation (No. 2018M633076).
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S.H., H.C., E.M., X.H., W.Y., and L.W. conceived and designed the experiments. M.E. and S.H. contributed reagents/materials/analysis tools. X.H., W.Y., Q.Z., Z.Z., Yi W., L.Q.L., L.T.L., Yu W., Z.G., J.G., H.Z., Y.L., S.Y., and T.H. performed the experiments and acquired and analyzed the data. X.H., W.Y., J.G., Q.Z., and Z.Z. prepared the figures and L.W., E.M., S.H., and H.C. helped revise them. X.H., S.H., H.C., W.Y., J.G., and L.W. drafted the paper, and S.H., X.H., E.M., H.C., W.Y., B.Z., L.L. and Yi W. revised it. All authors read and approved the final paper.
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He, X., Yang, W., Zeng, Z. et al. NLRP3-dependent pyroptosis is required for HIV-1 gp120-induced neuropathology. Cell Mol Immunol 17, 283–299 (2020). https://doi.org/10.1038/s41423-019-0260-y
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DOI: https://doi.org/10.1038/s41423-019-0260-y
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