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.

NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production?

Abstract

The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that activates caspase 1, leading to the processing and secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. The NLRP3 inflammasome is activated by a wide range of danger signals that derive not only from microorganisms but also from metabolic dysregulation. It is unclear how these highly varied stress signals can be detected by a single inflammasome. In this Opinion article, we review the different signalling pathways that have been proposed to engage the NLRP3 inflammasome and suggest a model in which one of the crucial elements for NLRP3 activation is the generation of reactive oxygen species (ROS).

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Mechanism of NLRP3 inflammasome complex formation.
Figure 2: The channel model of NLRP3 inflammasome activation.
Figure 3: The lysosome rupture model of NLRP3 inflammasome activation.
Figure 4: The reactive oxygen species model of NLRP3 inflammasome activation.

References

  1. Hammond-Kosack, K. E. & Jones, J. D. Resistance gene-dependent plant defense responses. Plant Cell 8, 1773–1791 (1996).

    Article  CAS  Google Scholar 

  2. Cohn, J., Sessa, G. & Martin, G. B. Innate immunity in plants. Curr. Opin. Immunol. 13, 55–62 (2001).

    Article  CAS  Google Scholar 

  3. Lam, E. Controlled cell death, plant survival and development. Nature Rev. Mol. Cell Biol. 5, 305–315 (2004).

    Article  CAS  Google Scholar 

  4. Miller, G. et al. The plant NADPH oxidase RBOHD mediates rapid systemic signaling in response to diverse stimuli. Sci. Signal. 2, ra45 (2009).

    PubMed  Google Scholar 

  5. Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).

    Article  CAS  Google Scholar 

  6. Adibhatla, R. M. & Hatcher, J. F. Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid. Redox Signal. 12, 125–169 (2010).

    Article  CAS  Google Scholar 

  7. Bryant, C. & Fitzgerald, K. A. Molecular mechanisms involved in inflammasome activation. Trends Cell Biol. 19, 455–464 (2009).

    Article  CAS  Google Scholar 

  8. Agostini, L. et al. NALP3 forms an IL-1β processing inflammasome with increased activity in Muckle–Wells auto-inflammatory disorder. Immunity 20, 319–325 (2004).

    Article  CAS  Google Scholar 

  9. Eder, C. Mechanisms of interleukin-1β release. Immunobiology 214, 543–553 (2009).

    Article  CAS  Google Scholar 

  10. Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).

    Article  CAS  Google Scholar 

  11. Perregaux, D. & Gabel, C. A. Interleukin-1β maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity. J. Biol. Chem. 269, 15195–15203 (1994).

    CAS  PubMed  Google Scholar 

  12. Pétrilli, V. et al. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 14, 1583–1589 (2007).

    Article  Google Scholar 

  13. Cain, K., Langlais, C., Sun, X. M., Brown, D. G. & Cohen, G. M. Physiological concentrations of K+ inhibit cytochrome c-dependent formation of the apoptosome. J. Biol. Chem. 276, 41985–41990 (2001).

    Article  CAS  Google Scholar 

  14. Pelegrin, P. & Surprenant, A. Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X7 receptor. EMBO J. 25, 5071–5082 (2006).

    Article  CAS  Google Scholar 

  15. Ferrari, D. et al. The P2X7 receptor: a key player in IL-1 processing and release. J. Immunol. 176, 3877–3883 (2006).

    Article  CAS  Google Scholar 

  16. Kanneganti, T.-D., Lamkanfi, M. & Nunez, G. Intracellular NOD-like receptors in host defense and disease. Immunity 27, 549–559 (2007).

    Article  CAS  Google Scholar 

  17. Sohl, G., Maxeiner, S. & Willecke, K. Expression and functions of neuronal gap junctions. Nature Rev. Neurosci. 6, 191–200 (2005).

    Article  Google Scholar 

  18. Marina-García, N. et al. Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2. J. Immunol. 180, 4050–4057 (2008).

    Article  Google Scholar 

  19. Kanneganti, T.-D. et al. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity 26, 433–443 (2007).

    Article  CAS  Google Scholar 

  20. Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunol. 9, 847–856 (2008).

    Article  CAS  Google Scholar 

  21. Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunol. 9, 857–865 (2008).

    Article  CAS  Google Scholar 

  22. Dostert, C. et al. Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS ONE 4, e6510 (2009).

    Article  Google Scholar 

  23. Newman, Z. L., Leppla, S. H. & Moayeri, M. CA-074Me protection against anthrax lethal toxin. Infect. Immun. 77, 4327–4336 (2009).

    Article  CAS  Google Scholar 

  24. Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nature Immunol. 11, 136–140 (2010).

    Article  CAS  Google Scholar 

  25. Dostert, C. et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008).

    Article  CAS  Google Scholar 

  26. Kowaltowski, A. J., de Souza-Pinto, N. C., Castilho, R. F. & Vercesi, A. E. Mitochondria and reactive oxygen species. Free Radic. Biol. Med. 47, 333–343 (2009).

    Article  CAS  Google Scholar 

  27. Krause, K.-H. & Bedard, K. NOX enzymes in immuno-inflammatory pathologies. Semin. Immunopathol. 30, 193–194 (2008).

    Article  Google Scholar 

  28. McDermott, M. F. & Tschopp, J. From inflammasomes to fevers, crystals and hypertension: how basic research explains inflammatory diseases. Trends Mol. Med. 13, 381–388 (2007).

    Article  CAS  Google Scholar 

  29. Walev, I., Reske, K., Palmer, M., Valeva, A. & Bhakdi, S. Potassium-inhibited processing of IL-1β in human monocytes. EMBO J. 14, 1607–1614 (1995).

    Article  CAS  Google Scholar 

  30. Meissner, F., Molawi, K. & Zychlinsky, A. Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nature Immunol. 9, 866–872 (2008).

    Article  CAS  Google Scholar 

  31. Kanneganti, T.-D. et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440, 233–236 (2006).

    Article  CAS  Google Scholar 

  32. Allen, I. C. et al. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity 30, 556–565 (2009).

    Article  CAS  Google Scholar 

  33. Joly, S. et al. Cutting edge: Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome. J. Immunol. 183, 3578–3581 (2009).

    Article  CAS  Google Scholar 

  34. Warren, S. E., Mao, D. P., Rodriguez, A. E., Miao, E. A. & Aderem, A. Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J. Immunol. 180, 7558–7564 (2008).

    Article  CAS  Google Scholar 

  35. Yamasaki, K. et al. NLRP3/cryopyrin is necessary for interleukin-1β (IL-1β) release in response to hyaluronan, an endogenous trigger of inflammation in response to injury. J. Biol. Chem. 284, 12762–12771 (2009).

    Article  CAS  Google Scholar 

  36. Cassel, S. L. et al. The Nalp3 inflammasome is essential for the development of silicosis. Proc. Natl Acad. Sci. USA 105, 9035–9040 (2008).

    Article  CAS  Google Scholar 

  37. Kool, M. et al. Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J. Immunol. 181, 3755–3759 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

J.T. is supported by grants from the Swiss National Science Foundation, by EU grants Mugen, Hermione, Apo-Sys and Apo-Train and by the Institute of Arthritis Research. K.S. is supported by a CJ Martin Fellowship from the Australian National Health and Medical Research Council (ID 490993).

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

Muckle–Wells syndrome

FURTHER INFORMATION

Jurg Tschopp's homepage

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Tschopp, J., Schroder, K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production?. Nat Rev Immunol 10, 210–215 (2010). https://doi.org/10.1038/nri2725

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2725

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing