Critical Role for Calcium Mobilization in Activation of the NLRP3 Inflammasome

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2012 Jun 27

PMID 22733741

Citations 461

Authors

Tomohiko Murakami

Johan Ockinger

Jiujiu Yu

Vanessa Byles

Aisleen McColl

Aldebaran M Hofer

Tiffany Horng

Affiliations

Soon will be listed here.

Abstract

The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome mediates production of inflammatory mediators, such as IL-1β and IL-18, and as such is implicated in a variety of inflammatory processes, including infection, sepsis, autoinflammatory diseases, and metabolic diseases. The proximal steps in NLRP3 inflammasome activation are not well understood. Here we elucidate a critical role for Ca(2+) mobilization in activation of the NLRP3 inflammasome by multiple stimuli. We demonstrate that blocking Ca(2+) mobilization inhibits assembly and activation of the NLRP3 inflammasome complex, and that during ATP stimulation Ca(2+) signaling is pivotal in promoting mitochondrial damage. C/EPB homologous protein, a transcription factor that can modulate Ca(2+) release from the endoplasmic reticulum, amplifies NLRP3 inflammasome activation, thus linking endoplasmic reticulum stress to activation of the NLRP3 inflammasome. Our findings support a model for NLRP3 inflammasome activation by Ca(2+)-mediated mitochondrial damage.

Citing Articles

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References

Menu P, Mayor A, Zhou R, Tardivel A, Ichijo H, Mori K . ER stress activates the NLRP3 inflammasome via an UPR-independent pathway. Cell Death Dis. 2012; 3:e261. PMC: 3270266. DOI: 10.1038/cddis.2011.132. View

Clapham D . Calcium signaling. Cell. 2007; 131(6):1047-58. DOI: 10.1016/j.cell.2007.11.028. View

Medzhitov R . Origin and physiological roles of inflammation. Nature. 2008; 454(7203):428-35. DOI: 10.1038/nature07201. View

Franchi L, Eigenbrod T, Munoz-Planillo R, Nunez G . The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol. 2009; 10(3):241-7. PMC: 2820724. DOI: 10.1038/ni.1703. View

Stober C, Lammas D, Li C, Kumararatne D, Lightman S, McArdle C . ATP-mediated killing of Mycobacterium bovis bacille Calmette-Guérin within human macrophages is calcium dependent and associated with the acidification of mycobacteria-containing phagosomes. J Immunol. 2001; 166(10):6276-86. DOI: 10.4049/jimmunol.166.10.6276. View

Feske S . Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol. 2007; 7(9):690-702. DOI: 10.1038/nri2152. View

Celsi F, Pizzo P, Brini M, Leo S, Fotino C, Pinton P . Mitochondria, calcium and cell death: a deadly triad in neurodegeneration. Biochim Biophys Acta. 2009; 1787(5):335-44. PMC: 2696196. DOI: 10.1016/j.bbabio.2009.02.021. View

Duewell P, Kono H, Rayner K, Sirois C, Vladimer G, Bauernfeind F . NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010; 464(7293):1357-61. PMC: 2946640. DOI: 10.1038/nature08938. View

Davis B, Wen H, Ting J . The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol. 2011; 29:707-35. PMC: 4067317. DOI: 10.1146/annurev-immunol-031210-101405. View

10.

Horng T, Barton G, Flavell R, Medzhitov R . The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature. 2002; 420(6913):329-33. DOI: 10.1038/nature01180. View

11.

Hoth M, Fanger C, Lewis R . Mitochondrial regulation of store-operated calcium signaling in T lymphocytes. J Cell Biol. 1997; 137(3):633-48. PMC: 2139882. DOI: 10.1083/jcb.137.3.633. View

12.

Duchen M . Mitochondria and calcium: from cell signalling to cell death. J Physiol. 2000; 529 Pt 1:57-68. PMC: 2270168. DOI: 10.1111/j.1469-7793.2000.00057.x. View

13.

Li G, Mongillo M, Chin K, Harding H, Ron D, Marks A . Role of ERO1-alpha-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis. J Cell Biol. 2009; 186(6):783-92. PMC: 2753154. DOI: 10.1083/jcb.200904060. View

14.

Feldmeyer L, Keller M, Niklaus G, Hohl D, Werner S, Beer H . The inflammasome mediates UVB-induced activation and secretion of interleukin-1beta by keratinocytes. Curr Biol. 2007; 17(13):1140-5. DOI: 10.1016/j.cub.2007.05.074. View

15.

Hornung V, Bauernfeind F, Halle A, Samstad E, Kono H, Rock K . Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008; 9(8):847-56. PMC: 2834784. DOI: 10.1038/ni.1631. View

16.

Gilabert J, Bakowski D, Parekh A . Energized mitochondria increase the dynamic range over which inositol 1,4,5-trisphosphate activates store-operated calcium influx. EMBO J. 2001; 20(11):2672-9. PMC: 125482. DOI: 10.1093/emboj/20.11.2672. View

17.

Haller T, Dietl P, Deetjen P, Volkl H . The lysosomal compartment as intracellular calcium store in MDCK cells: a possible involvement in InsP3-mediated Ca2+ release. Cell Calcium. 1996; 19(2):157-65. DOI: 10.1016/s0143-4160(96)90084-6. View

18.

Fu S, Yang L, Li P, Hofmann O, Dicker L, Hide W . Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature. 2011; 473(7348):528-31. PMC: 3102791. DOI: 10.1038/nature09968. View

19.

Okubo Y, Kakizawa S, Hirose K, Iino M . Visualization of IP(3) dynamics reveals a novel AMPA receptor-triggered IP(3) production pathway mediated by voltage-dependent Ca(2+) influx in Purkinje cells. Neuron. 2001; 32(1):113-22. DOI: 10.1016/s0896-6273(01)00464-0. View

20.

Schroder K, Tschopp J . The inflammasomes. Cell. 2010; 140(6):821-32. DOI: 10.1016/j.cell.2010.01.040. View