NF-κB/ROS and ERK pathways regulate NLRP3 inflammasome activation in Listeria monocytogenes infected BV2 microglia cells

Abstract

Listeria monocytogenes is a food-borne pathogen responsible for neurolisteriosis, which is potentially lethal in immunocompromised individuals. Microglia are the main target cells for L. monocytogenes in central nervous system (CNS). However, the precise mechanisms by which they trigger neuroinflammatory processes remain unknown. The BV2 microglial cell line and a murine model of L. monocytogenes infection were used for experiments in this study. Listeria monocytogenes induced pyroptosis and nucleotide binding and oligomerization, leucine-rich repeat, pyrin domain-containing 3 (NLRP3) inflammasome activation in BV2. Pharmacological inhibition of the NLRP3 inflammasome attenuated L. monocytogenes-induced pyroptosis. Moreover, inhibition of nuclear factor kappa-B (NF-κB) and extracellular regulated protein kinases (ERK) pathways induced a decrease in caspase1 activation and mature IL-1β-17 secretion. Our collective findings support critical involvement of the NLRP3 inflammasome in L. monocytogenes-induced neuroinflammation and, to an extent, ROS production. In addition, ERK and NF-κB signaling play an important role in activation of the NLRP3 inflammasome, both in vitro and in vivo.

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References

  1. Charlier, C., Perrodeau, É., Leclercq, A., Cazenave, B., Pilmis, B., Henry, B., Lopes, A., Maury, M.M., Moura, A., Goffinet, F., et al. 2017. Clinical features and prognostic factors of listeriosis: the MONALISA national prospective cohort study. Lancet Infect. Dis. 17, 510–519.

    PubMed  Article  Google Scholar 

  2. Chei, S., Oh, H.J., Song, J.H., Seo, Y.J., Lee, K., Kim, K.J., and Lee, B.Y. 2020. Spirulina maxima extract prevents activation of the NLRP3 inflammasome by inhibiting ERK signaling. Sci. Rep. 10, 2075.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. Chen, H., Lu, Y., Cao, Z., Ma, Q., Pi, H., Fang, Y., Yu, Z., Hu, H., and Zhou, Z. 2016. Cadmium induces NLRP3 inflammasome-dependent pyroptosis in vascular endothelial cells. Toxicol. Lett. 246, 7–16.

    CAS  PubMed  Article  Google Scholar 

  4. Cipollina, G., Davari Serej, A., Di Nolfi, G., Gazzano, A., Marsala, A., Spatafora, M.G., and Peviani, M. 2020. Heterogeneity of neuro-inflammatory responses in amyotrophic lateral sclerosis: a challenge or an opportunity? Int. J. Mol. Sci. 21, 7923.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  5. de Rivero Vaccari, J.P., Dietrich, W.D., and Keane, R.W. 2014. Activation and regulation of cellular inflammasomes: gaps in our knowledge for central nervous system injury. J. Cereb. Blood Flow Metab. 34, 369–375.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. Deckert, M., Virna, S., Sakowicz-Burkiewicz, M., Lutjen, S., Soltek, S., Bluethmann, H., and Schlüter, D. 2007. Interleukin-1 receptor type 1 is essential for control of cerebral but not systemic Listeriosis. Am. J. Pathol. 170, 990–1002.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Dickstein, Y., Oster, Y., Shimon, O., Nesher, L., Yahav, D., Wiener-Well, Y., Cohen, R., Ben-Ami, R., Weinberger, M., Rahav, G., et al. 2019. Antibiotic treatment for invasive nonpregnancy-associated listeriosis and mortality: a retrospective cohort study. Eur. J. Clin. Microbiol. Infect. Dis. 38, 2243–2251.

    CAS  PubMed  Article  Google Scholar 

  8. Dramsi, S., Lévi, S., Triller, A., and Cossart, P. 1998. Entry of Listeria monocytogenes into neurons occurs by cell-to-cell spread: an in vitro study. Infect. Immun. 66, 4461–4468.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Eme-Scolan, E. and Dando, S.J. 2020. Tools and approaches for studying microglia in vivo. Front. Immunol. 11, 583647.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Frande-Cabanes, E., Fernandez-Prieto, L., Calderon-Gonzalez, R., Rodríguez-Del Rio, E., Yañez-Diaz, S., López-Fanarraga, M., and Alvarez-Dominguez, C. 2014. Dissociation of innate immune responses in microglia infected with Listeria monocytogenes. Glia 62, 233–246.

    PubMed  Article  PubMed Central  Google Scholar 

  11. Guldimann, C., Bärtschi, M., Frey, J., Zurbriggen, A., Seuberlich, T., and Oevermann, A. 2015. Increased spread and replication efficiency of Listeria monocytogenes in organotypic brain-slices is related to multilocus variable number of tandem repeat analysis (MLVA) complex. BMC Microbiol. 15, 134.

    PubMed  PubMed Central  Article  Google Scholar 

  12. Hayward, J.A., Mathur, A., Ngo, C., and Man, S.M. 2018. Cytosolic recognition of microbes and pathogens: inflammasomes in action. Microbiol. Mol. Biol. Rev. 12, e00015–18.

    Google Scholar 

  13. He, X., Yang, W., Zeng, Z., Wei, Y., Gao, J., Zhang, B., Li, L., Liu, L., Wan, Y., Zeng, Q., et al. 2020. NLRP3-dependent pyroptosis is required for HIV-1 gp120-induced neuropathology. Cell. Mol. Immunol. 17, 283–299.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. Kaushik, D.K., Gupta, M., Kumawat, K.L., and Basu, A. 2012. NLRP3 inflammasome: key mediator of neuroinflammation in murine Japanese encephalitis. PLoS ONE 7, e32270.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Keane, L., Antignano, I., Riechers, S.P., Zollinger, R., Dumas, A.A., Offermann, N., Bernis, M.E., Russ, J., Graelmann, F., McCormick, P.N., et al. 2020. mTOR-dependent translation amplifies microglia priming in aging mice. J. Clin. Invest. 131, 132727.

    Article  Google Scholar 

  16. Kim, S., Bauernfeind, F., Ablasser, A., Hartmann, G., Fitzgerald, K.A., Latz, E., and Hornung, V. 2010. Listeria monocytogenes is sensed by the NLRP3 and AIM2 inflammasome. Eur. J. Immunol. 40, 1545–1551.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Kim, J.Y., Paton, J.C., Briles, D.E., Rhee, D.K., and Pyo, S. 2015. Streptococcus pneumoniae induces pyroptosis through the regulation of autophagy in murine microglia. Oncotarget. 6, 44161–44178.

    PubMed  PubMed Central  Article  Google Scholar 

  18. Liu, X., Zhang, Z., Ruan, J., Pan, Y., Magupalli, V.G., Wu, H., and Lieberman, J. 2016. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Mailles, A., Lecuit, M., Goulet, V., Leclercq, A., and Stahl, J.P. 2011. Listeria monocytogenes encephalitis in France. Med. Mal. Infect. 41, 594–601.

    CAS  PubMed  Article  Google Scholar 

  20. Mathur, A., Feng, S., Hayward, J.A., Ngo, C., Fox, D., Atmosukarto, I.I., Price, J.D., Schauer, K., Märtbauer, E., Robertson, A.A.B., et al. 2019. A multicomponent toxin from Bacillus cereus incites inflammation and shapes host outcome via the NLRP3 inflammasome. Nat. Microbiol. 4, 362–374.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. Ollà, I., Santos-Galindo, M., Elorza, A., and Lucas, J.J. 2020. P2X7 receptor upregulation in Huntington’s disease brains. Front. Mol. Neurosci. 13, 567430.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. Pagliano, P., Arslan, F., and Ascione, T. 2017. Epidemiology and treatment of the commonest form of listeriosis: meningitis and bacteraemia. Infez. Med. 25, 210–216.

    PubMed  PubMed Central  Google Scholar 

  23. Peters, M. and Hewicker-Trautwein, M. 1994. Infection of murine fetal brain cell cultures with Listeria monocytogenes. Vet. Microbiol. 41, 19–28.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. Radoshevich, L. and Cossart, P. 2018. Listeria monocytogenes: towards a complete picture of its physiology and pathogenesis. Nat. Rev. Microbiol. 16, 32–46.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. Schlüter, D., Buck, C., Reiter, S., Meyer, T., Hof, H., and Deckert-Schlüter, M. 1999. Immune reactions to Listeria monocytogenes in the brain. Immunobiology 201, 188–195.

    PubMed  Article  PubMed Central  Google Scholar 

  26. Scobie, A., Kanagarajah, S., Harris, R.J., Byrne, L., Amar, C., Grant, K., and Godbole, G. 2019. Mortality risk factors for listeriosis — a 10 year review of non-pregnancy associated cases in England 2006–2015. J. Infect. 78, 208–214.

    PubMed  Article  PubMed Central  Google Scholar 

  27. Shi, J., Zhao, Y., Wang, K., Shi, X., Wang, Y., Huang, H., Zhuang, Y., Cai, T., Wang, F., and Shao, F. 2015. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  29. Stewart, M.K. and Cookson, B.T. 2016. Evasion and interference intracellular pathogens modulate caspase-dependent inflammatory responses. Nat. Rev. Microbiol. 14, 346–359.

    CAS  PubMed  Article  Google Scholar 

  30. Swanson, K.V., Deng, M., and Ting, J.P.Y. 2019. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 19, 477–489.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Swaroop, S., Mahadevan, A., Shankar, S.K., Adlakha, Y.K., and Basu, A. 2018. HSP60 critically regulates endogenous IL-1β production in activated microglia by stimulating NLRP3 inflammasome pathway. J. Neuroinflammation 15, 177.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. Tiri, B., Priante, G., Saraca, L.M., Martella, L.A., Cappanera, S., and Francisci, D. 2018. Listeria monocytogenes brain abscess: controversial issues for the treatment-two cases and literature review. Case Rep. Infect. Dis. 2018, 6549496.

    PubMed  PubMed Central  Google Scholar 

  33. Tricarico, P.M., Caracciolo, I., Crovella, S., and D’Agaro, P. 2017. Zika virus induces inflammasome activation in the glial cell line U87-MG. Biochem. Biophys. Res. Commun. 28, 597–602.

    Article  CAS  Google Scholar 

  34. Tsukahara, T., Haniu, H., Uemura, T., and Matsuda, Y. 2020. Therapeutic potential of porcine liver decomposition product: new insights and perspectives for microglia-mediated neuroinflammation in neurodegenerative diseases. Biomedicines 8, 446.

    CAS  PubMed Central  Article  Google Scholar 

  35. von Moltke, J., Ayres, J.S., Kofoed, E.M., Chavarría-Smith, J., and Vance, R.E. 2013. Recognition of bacteria by inflammasome. Annu. Rev. Immunol. 31, 73–106.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. Wang, C., Hockerman, S., Jacobsen, E.J., Alippe, Y., Selness, S.R., Hope, H.R., Hirsch, J.L., Mnich, S.J., Saabye, M.J., Hood, W.F., et al. 2018. Selective inhibition of the p38α MAPK-MK2 axis inhibits inflammatory cues including inflammasome priming signals. J. Exp. Med. 215, 1315–1325.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Warren, S.E., Mao, D.P., Rodriguez, A.E., Miao, E.A., and Aderem, A. 2008. Multiple nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J. Immunol. 180, 7558–7564.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. Wu, J., Fernandes-Alnemri, T., and Alnemri, E.S. 2010. Involvement of the AIM2, NLRC4, and NLRP3 inflammasomes in caspase-1 activation by Listeria monocytogenes. J. Clin. Immunol. 30, 693–702.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Yin, R., Zhu, X., Wang, J., Yang, S., Ma, A., Xiao, Q., Song, J., and Pan, X. 2019. MicroRNA-155 promotes the ox-LDL-induced activation of NLRP3 inflammasomes via the ERK1/2 pathway in THP-1 macrophages and aggravates atherosclerosis in ApoE-/-mice. Ann. Palliat. Med. 8, 676–689.

    PubMed  Article  Google Scholar 

  40. Yuan, L., Zhu, Y.R., Lin, L., Huang, S., Jiang, X.G., and Chen, S.X. 2021. NLRP3 inflammasome mediates pyroptosis caused by Listeria monocytogenes infection in mice and macrophages. J. Jiangsu Univ. Med. Ed. 31, 307–312. DOI: https://doi.org/10.13312/j.issn.1671-7783.y200204

    Google Scholar 

  41. Zhou, R., Yazdi, A.S., Menu, P., and Tschopp, J. 2010. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the Basic Platform Project of the Ministry of Science and Technology of China (No. TDRC-2019-194-30).

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Correspondence to Shengxia Chen.

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All authors have no conflicts of interest to declare and no commercial or financial interest in the products described in this article.

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Yuan, L., Zhu, Y., Huang, S. et al. NF-κB/ROS and ERK pathways regulate NLRP3 inflammasome activation in Listeria monocytogenes infected BV2 microglia cells. J Microbiol. 59, 771–781 (2021). https://doi.org/10.1007/s12275-021-0692-9

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Keywords

  • Listeria monocytogenes
  • nucleotide binding and oligomerization
  • leucine-rich repeat
  • pyrin domain-containing 3 (NLRP3) inflammasome
  • pyroptosis
  • microglia
  • nuclear factor kappa-B (NF-κB)
  • reactive oxygen species (ROS)
  • mitogen-activated protein kinase (MAPK)