Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Saylor, D. et al. HIV-associated neurocognitive disorder—pathogenesis and prospects for treatment. Nat. Rev. Neurol. 12, 234–248 (2016).

    Article  Google Scholar 

  2. Clifford, D. B. & Ances, B. M. HIV-associated neurocognitive disorder. Lancet Infect. Dis. 13, 976–986 (2013).

    Article  Google Scholar 

  3. Eggers, C. et al. HIV-1-associated neurocognitive disorder: epidemiology, pathogenesis, diagnosis, and treatment. J. Neurol. 264, 1715–1727 (2017).

    Article  Google Scholar 

  4. Brenneman, D. E. et al. Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature 335, 639–642 (1988).

    Article  CAS  Google Scholar 

  5. Toggas, S. M. et al. Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature 367, 188–193 (1994).

    Article  CAS  Google Scholar 

  6. Kaul, M., Garden, G. A. & Lipton, S. A. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410, 988–994 (2001).

    Article  CAS  Google Scholar 

  7. Capo-Velez, C. M., Morales-Vargas, B., Garcia-Gonzalez, A. & Grajales-Reyes, J. G. The alpha7-nicotinic receptor contributes to gp120-induced neurotoxicity: implications in HIV-associated neurocognitive disorders. Sci. Rep. 8, 1829 (2018).

    Article  Google Scholar 

  8. D’Hooge, R., Franck, F., Mucke, L. & De Deyn, P. P. Age-related behavioural deficits in transgenic mice expressing the HIV-1 coat protein gp120. Eur. J. Neurosci. 11, 4398–gp4402 (1999).

    Article  Google Scholar 

  9. Gonzalez-Scarano, F. & Martin-Garcia, J. The neuropathogenesis of AIDS. Nat. Rev. Immunol. 5, 69–81 (2005).

    Article  CAS  Google Scholar 

  10. Chen, N. C., Partridge, A. T., Sell, C., Torres, C. & Martin-Garcia, J. Fate of microglia during HIV-1 infection: from activation to senescence? Glia 65, 431–446 (2017).

    Article  Google Scholar 

  11. Heneka, M. T., McManus, R. M. & Latz, E. Inflammasome signalling in brain function and neurodegenerative disease. Nat. Rev. Neurosci. 19, 610–621 (2018).

    Article  CAS  Google Scholar 

  12. Mangan, M. S. J. et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat. Rev. Drug Disco. 17, 588–606 (2018).

    Article  CAS  Google Scholar 

  13. Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158 (2016).

    Article  CAS  Google Scholar 

  14. Song, L., Pei, L., Yao, S., Wu, Y. & Shang, Y. NLRP3 inflammasome in neurological diseases, from functions to therapies. Front Cell Neurosci. 11, 63 (2017).

    Article  Google Scholar 

  15. Allan, S. M., Tyrrell, P. J. & Rothwell, N. J. Interleukin-1 and neuronal injury. Nat. Rev. Immunol. 5, 629–640 (2005).

    Article  CAS  Google Scholar 

  16. Heneka, M. T. et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013).

    Article  CAS  Google Scholar 

  17. Gordon, R. & Albornoz, E. A. Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice. Sci. Transl. Med 10, eaah4066 (2018).

    Article  Google Scholar 

  18. Walsh, J. G. et al. Rapid inflammasome activation in microglia contributes to brain disease in HIV/AIDS. Retrovirology 11, 35 (2014).

    Article  Google Scholar 

  19. Kaul, M. & Lipton, S. A. Mechanisms of neuronal injury and death in HIV-1 associated dementia. Curr. HIV Res. 4, 307–318 (2006).

    Article  CAS  Google Scholar 

  20. Michael, N. L. & Moore, J. P. HIV-1 entry inhibitors: evading the issue. Nat. Med. 5, 740–742 (1999).

    Article  CAS  Google Scholar 

  21. Maung, R. et al. CCR5 knockout prevents neuronal injury and behavioral impairment induced in a transgenic mouse model by a CXCR4-using HIV-1 glycoprotein 120. J. Immunol. 193, 1895–1910 (2014).

    Article  CAS  Google Scholar 

  22. Sun, N.-N. et al. Mir-21 mediates the inhibitory effect of Ang (1–7) on AngII-induced NLRP3 inflammasome activation by targeting Spry1 in lung fibroblasts. Sci. Rep. 7, 14369 (2017).

    Article  Google Scholar 

  23. Doitsh, G. et al. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature 505, 509–514 (2014).

    Article  CAS  Google Scholar 

  24. Ahmad, F. et al. Evidence of inflammasome activation and formation of monocyte-derived ASC specks in HIV-1 positive patients. Aids 32, 299–307 (2018).

    Article  CAS  Google Scholar 

  25. Coll, R. C. et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 21, 248–255 (2015).

    Article  CAS  Google Scholar 

  26. Afonina, I. S., Zhong, Z., Karin, M. & Beyaert, R. Limiting inflammation-the negative regulation of NF-kappaB and the NLRP3 inflammasome. Nat. Immunol. 18, 861–869 (2017).

    Article  CAS  Google Scholar 

  27. Liu, J., Xu, C., Chen, L., Xu, P. & Xiong, H. Involvement of Kv1.3 and p38 MAPK signaling in HIV-1 glycoprotein 120-induced microglia neurotoxicity. Cell Death Dis. 3, e254 (2012).

    Article  CAS  Google Scholar 

  28. Xu, C. et al. HIV-1 gp120 enhances outward potassium current via CXCR4 and cAMP-dependent protein kinase A signaling in cultured rat microglia. Glia 59, 997–1007 (2011).

    Article  Google Scholar 

  29. Ogishi, M. & Yotsuyanagi, H. Prediction of HIV-associated neurocognitive disorder (HAND) from three genetic features of envelope gp120 glycoprotein. Retrovirology 15, 12 (2018).

    Article  Google Scholar 

  30. Barak, O. et al. Involvement of brain cytokines in the neurobehavioral disturbances induced by HIV-1 glycoprotein120. Brain Res. 933, 98–108 (2002).

    Article  CAS  Google Scholar 

  31. Thaney, V. E. et al. Transgenic mice expressing HIV-1 envelope protein gp120 in the brain as an animal model in neuroAIDS research. J. Neurovirol. 24, 156–167 (2018).

    Article  CAS  Google Scholar 

  32. Ransohoff, R. M. A polarizing question: do M1 and M2 microglia exist? Nat. Neurosci. 19, 987–991 (2016).

    Article  CAS  Google Scholar 

  33. Andersen, I. L., Boe, K. E., Foerevik, G., Janczak, A. M. & Bakken, M. Behavioural evaluation of methods for assessing fear responses in weaned pigs. Appl Anim. Behav. Sci. 69, 227–240 (2000).

    Article  CAS  Google Scholar 

  34. Baroja-Mazo, A. et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat. Immunol. 15, 738–748 (2014).

    Article  CAS  Google Scholar 

  35. Chivero, E. T., Guo, M. L. & Periyasamy, P. HIV-1 Tat primes and activates microglial NLRP3 inflammasome-mediated neuroinflammation. J. Neurosci. 37, 3599–3609 (2017).

    Article  CAS  Google Scholar 

  36. Ichinohe, T., Pang, I. K. & Iwasaki, A. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat. Immunol. 11, 404–410 (2010).

    Article  CAS  Google Scholar 

  37. Hafner-Bratkovic, I., Bencina, M., Fitzgerald, K. A., Golenbock, D. & Jerala, R. NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1beta and neuronal toxicity. Cell Mol. Life Sci. 69, 4215–4228 (2012).

    Article  CAS  Google Scholar 

  38. Negash, A. A. et al. IL-1beta production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease. PLoS Pathog. 9, e1003330 (2013).

    Article  CAS  Google Scholar 

  39. Chandy, K. G. & Norton, R. S. Peptide blockers of Kv1.3 channels in T cells as therapeutics for autoimmune disease. Curr. Opin. Chem. Biol. 38, 97–107 (2017).

    Article  CAS  Google Scholar 

  40. Chiang, E. Y. et al. Potassium channels Kv1.3 and KCa3.1 cooperatively and compensatorily regulate antigen-specific memory T cell functions. Nat. Commun. 8, 14644 (2017).

    Article  Google Scholar 

  41. Maezawa, I. et al. Kv1.3 inhibition as a potential microglia-targeted therapy for Alzheimer’s disease: preclinical proof of concept. Brain 141, 596–612 (2018).

    Article  Google Scholar 

  42. Upadhyay, S. K. et al. Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance. Proc. Natl Acad. Sci. USA 110, E2239–E2248 (2013).

    Article  CAS  Google Scholar 

  43. Di Lucente, J., Nguyen, H. M. & Wulff, H. The voltage-gated potassium channel Kv1.3 is required for microglial pro-inflammatory activation in vivo. Glia 66, 1881–1895 (2018).

    Article  Google Scholar 

  44. Liu, X. & Quan, N. Microglia and CNS Interleukin-1: Beyond Immunological Concepts. Front Neurol. 9, 8 (2018).

    Article  Google Scholar 

  45. Corasaniti, M. T. et al. 17beta-estradiol reduces neuronal apoptosis induced by HIV-1 gp120 in the neocortex of rat. Neurotoxicology 26, 893–903 (2005).

    Article  CAS  Google Scholar 

  46. Zhou, C. et al. Interleukin-1beta downregulates the L-type Ca2 + channel activity by depressing the expression of channel protein in cortical neurons. J. Cell Physiol. 206, 799–806 (2006).

    Article  CAS  Google Scholar 

  47. Yu, J. et al. IL-1beta stimulates brain-derived neurotrophic factor production in eutopic endometriosis stromal cell cultures: a model for cytokine regulation of neuroangiogenesis. Am. J. Pathol. 188, 2281–2292 (2018).

    Article  CAS  Google Scholar 

  48. Corasaniti, M. T. et al. Evidence that increases of mitochondrial immunoreactive IL-1beta by HIV-1gp120 implicate in situ cleavage of pro-IL-1beta in the neocortex of rat. J. Neurochem. 78, 611–618 (2001).

    Article  CAS  Google Scholar 

  49. Russo, R. et al. Evidence implicating matrix metalloproteinases in the mechanism underlying accumulation of IL-1beta and neuronal apoptosis in the neocortex of HIV/gp120-exposed rats. Int Rev. Neurobiol. 82, 407–421 (2007).

    Article  CAS  Google Scholar 

  50. Lipton, S. A. & Gendelman, H. E. Seminars in medicine of the Beth Israel Hospital, Boston. Dementia associated with the acquired immunodeficiency syndrome. N. Engl. J. Med. 332, 934–940 (1995).

    Article  CAS  Google Scholar 

  51. Block, M. L., Zecca, L. & Hong, J. S. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8, 57–69 (2007).

    Article  CAS  Google Scholar 

  52. Valderrama, J. A., Riestra, A. M., Gao, N. J. & LaRock, C. N. Group A streptococcal M protein activates the NLRP3 inflammasome. Nat. Microbiol. 2, 1425–1434 (2017).

    Article  CAS  Google Scholar 

  53. Ashraf, T. et al. Role of anti-inflammatory compounds in human immunodeficiency virus-1 glycoprotein120-mediated brain inflammation. J. Neuroinflamm. 11, 91 (2014).

    Article  Google Scholar 

  54. Bachis, A., Cruz, M. I. & Mocchetti, I. M‐tropic HIV envelope protein gp120 exhibits a different neuropathological profile than T‐tropic gp120 in rat striatum. Eur. J. Neurosci. 32, 570–578 (2010).

    Article  Google Scholar 

  55. Wang, Y., Liao, J., Tang, S. J., Shu, J. & Zhang, W. HIV-1gp120 upregulates brain-derived neurotrophic factor (BDNF) expression in BV2 cells via the Wnt/β-catenin signaling pathway. J. Mol. Neurosci. 62, 199–208 (2017).

    Article  CAS  Google Scholar 

  56. Luo, W., Fang, W., Li, S. & Yao, K. Aberrant expression of nuclear vimentin and related epithelial–mesenchymal transition markers in nasopharyngeal carcinoma. Int. J. Cancer 131, 1863–1873 (2012).

    Article  CAS  Google Scholar 

  57. Huang, S.-H. et al. Vimentin, a Novel NF-κB regulator, is required for meningitic Escherichia coli K1-induced pathogen invasion and PMN transmigration across the blood-brain barrier. PloS One 11, e0162641 (2016).

    Article  Google Scholar 

  58. Dos Santos, G. et al. Vimentin regulates activation of the NLRP3 inflammasome. Nat. Commun. 6, 6574 (2015).

    Article  Google Scholar 

  59. Hol, E. M. & Pekny, M. Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr. Opin. Cell Biol. 32, 121–130 (2015).

    Article  CAS  Google Scholar 

  60. El-Barbary, A. M., Kassem, E. M., El-Sergany, M. A., SALWA, A. & Eltomey, M. A. Association of anti-modified citrullinated vimentin with subclinical atherosclerosis in early rheumatoid arthritis compared with anti-cyclic citrullinated peptide. J. Rheumatol. 38, 828–834 (2011).

    Article  CAS  Google Scholar 

  61. Thomas, E. K. et al. Anti-idiotypic antibody to the V3 domain of gp120 binds to vimentin: a possible role of intermediate filaments in the early steps of HIV-1 infection cycle. Viral Immunol. 9, 73–87 (1996).

    Article  CAS  Google Scholar 

  62. Noda, H., Takeuchi, H., Mizuno, T. & Suzumura, A. Fingolimod phosphate promotes the neuroprotective effects of microglia. J. Neuroimmunol. 256, 13–18 (2013).

    Article  CAS  Google Scholar 

  63. Meeker, R. B., Poulton, W., Clary, G., Schriver, M. & Longo, F. M. Novel p75 neurotrophin receptor ligand stabilizes neuronal calcium, preserves mitochondrial movement and protects against HIV associated neuropathogenesis. Exp. Neurol. 275, 182–198 (2016).

    Article  CAS  Google Scholar 

  64. Dreyer, E. B., Kaiser, P. K., Offermann, J. T. & Lipton, S. A. HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science 248, 364–367 (1990).

    Article  CAS  Google Scholar 

  65. Ashkenazi, A. et al. Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 545, 108–111 (2017).

    Article  CAS  Google Scholar 

  66. Moss, P. J. et al. Macrophage–sensory neuronal interaction in HIV-1 gp120-induced neurotoxicity. Br. J. Anaesth. 114, 499–508 (2014).

    Article  Google Scholar 

  67. Keswani, S. C. et al. Schwann cell chemokine receptors mediate HIV-1 gp120 toxicity to sensory neurons. Ann. Neurol. 54, 287–296 (2003).

    Article  CAS  Google Scholar 

  68. Higgins, S., Lee, J. S., Ha, L. & Lim, J. Y. Inducing neurite outgrowth by mechanical cell stretch. BioResearch Open Access 2, 212–216 (2013).

    Article  CAS  Google Scholar 

Download references

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).

Author information

Author notes

  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

Authors
  1. Xiaolong He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weijun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhijie Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jie Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Li Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Liqun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yu Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qing Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zelong Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Liting Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hanyun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yubin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Shaojie Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Tongtong Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Lixian Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Eliezer Masliah
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Shenghe Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Hong Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding authors

Correspondence to Shenghe Huang or Hong Cao.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-019-0260-y

Keywords

This article is cited by

Search

Advanced search

Quick links