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

  • Cell Mol Immunol. 2020 Mar;17(3):283-299. doi: 10.1038/s41423-019-0260-y.
Xiaolong He   #  1 ,  Weijun Yang   #  1 ,  Zhijie Zeng   #  1 ,  Yi Wei   #  1 ,  Jie Gao  1 ,  Bao Zhang  1 ,  Li Li  2 ,  Liqun Liu  3 ,  Yu Wan  1 ,  Qing Zeng  1 ,  Zelong Gong  1 ,  Liting Liu  4 ,  Hanyun Zhang  1 ,  Yubin Li  1 ,  Shaojie Yang  1 ,  Tongtong Hu  1 ,  Lixian Wu  4 ,  Eliezer Masliah  5  6 ,  Shenghe Huang  7  8  9 ,  Hong Cao  10
Affiliations
  • 1. Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China.
  • 2. Kunming Key Laboratory of Children Infection and Immunity, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming, Yunnan, 650228, China.
  • 3. Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
  • 4. Department of Medical Microbiology and Immunology, Dali University, Dali, 671000, China.
  • 5. Division of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 6. Departments of Neuroscience and Pathology, University of California, San Diego, La Jolla, CA, 92093, USA.
  • 7. Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China. [email protected].
  • 8. Kunming Key Laboratory of Children Infection and Immunity, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming, Yunnan, 650228, China. [email protected].
  • 9. Saban Research Institute, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, 90027, USA. [email protected].
  • 10. Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China. [email protected].
  • # Contributed equally.
PMID: 31320730 DOI: 10.1038/s41423-019-0260-y
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.

Keywords
HIV-1 gp120; HIV-associated neurocognitive disorder; NLRP3 inflammasome; Neuroinflammation; Neuropathology.
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