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NLRP3-dependent pyroptosis is required for HIV-1 gp120-induced neuropathology

Cellular & Molecular Immunology volume 17, pages 283–299 (2020)Cite this article

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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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    The original online version of this article was revised: Fig 8d and Supplementary Figure 5d have been updated.

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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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  1. These authors contributed equally: Xiaolong He, Weijun Yang, Zhijie Zeng, Yi Wei

Authors and Affiliations

  1. Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China

    Xiaolong He, Weijun Yang, Zhijie Zeng, Yi Wei, Jie Gao, Bao Zhang, Yu Wan, Qing Zeng, Zelong Gong, Hanyun Zhang, Yubin Li, Shaojie Yang, Tongtong Hu, Shenghe Huang & Hong Cao

  2. Kunming Key Laboratory of Children Infection and Immunity, Yunnan Institute of Pediatrics, Kunming Children’s Hospital, Kunming, Yunnan, 650228, China

    Li Li & Shenghe Huang

  3. Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, 410011, China

    Liqun Liu

  4. Department of Medical Microbiology and Immunology, Dali University, Dali, 671000, China

    Liting Liu & Lixian Wu

  5. Division of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA

    Eliezer Masliah

  6. Departments of Neuroscience and Pathology, University of California, San Diego, La Jolla, CA, 92093, USA

    Eliezer Masliah

  7. Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, 90027, USA

    Shenghe Huang

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Contributions

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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Correspondence to Shenghe Huang or Hong Cao.

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The authors declare no competing interests.

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The original online version of this article was revised: Fig 8d and Supplementary Figure 5d have been updated.

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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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