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).
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References
Hammond-Kosack, K. E. & Jones, J. D. Resistance gene-dependent plant defense responses. Plant Cell 8, 1773–1791 (1996).
Cohn, J., Sessa, G. & Martin, G. B. Innate immunity in plants. Curr. Opin. Immunol. 13, 55–62 (2001).
Lam, E. Controlled cell death, plant survival and development. Nature Rev. Mol. Cell Biol. 5, 305–315 (2004).
Miller, G. et al. The plant NADPH oxidase RBOHD mediates rapid systemic signaling in response to diverse stimuli. Sci. Signal. 2, ra45 (2009).
Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).
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).
Bryant, C. & Fitzgerald, K. A. Molecular mechanisms involved in inflammasome activation. Trends Cell Biol. 19, 455–464 (2009).
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).
Eder, C. Mechanisms of interleukin-1β release. Immunobiology 214, 543–553 (2009).
Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).
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).
Pétrilli, V. et al. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 14, 1583–1589 (2007).
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).
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).
Ferrari, D. et al. The P2X7 receptor: a key player in IL-1 processing and release. J. Immunol. 176, 3877–3883 (2006).
Kanneganti, T.-D., Lamkanfi, M. & Nunez, G. Intracellular NOD-like receptors in host defense and disease. Immunity 27, 549–559 (2007).
Sohl, G., Maxeiner, S. & Willecke, K. Expression and functions of neuronal gap junctions. Nature Rev. Neurosci. 6, 191–200 (2005).
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).
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).
Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunol. 9, 847–856 (2008).
Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunol. 9, 857–865 (2008).
Dostert, C. et al. Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS ONE 4, e6510 (2009).
Newman, Z. L., Leppla, S. H. & Moayeri, M. CA-074Me protection against anthrax lethal toxin. Infect. Immun. 77, 4327–4336 (2009).
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).
Dostert, C. et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008).
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).
Krause, K.-H. & Bedard, K. NOX enzymes in immuno-inflammatory pathologies. Semin. Immunopathol. 30, 193–194 (2008).
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).
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).
Meissner, F., Molawi, K. & Zychlinsky, A. Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nature Immunol. 9, 866–872 (2008).
Kanneganti, T.-D. et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440, 233–236 (2006).
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).
Joly, S. et al. Cutting edge: Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome. J. Immunol. 183, 3578–3581 (2009).
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).
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).
Cassel, S. L. et al. The Nalp3 inflammasome is essential for the development of silicosis. Proc. Natl Acad. Sci. USA 105, 9035–9040 (2008).
Kool, M. et al. Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J. Immunol. 181, 3755–3759 (2008).
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).
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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
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DOI: https://doi.org/10.1038/nri2725