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Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors - Nature Medicine

  • ️Zitvogel, Laurence
  • ️Sun Sep 20 2009

References

  1. Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    Article  CAS  Google Scholar 

  2. Savill, J., Dransfield, I., Gregory, C. & Haslett, C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat. Rev. Immunol. 2, 965–975 (2002).

    Article  CAS  Google Scholar 

  3. Leadbetter, E.A. et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002).

    Article  CAS  Google Scholar 

  4. Lau, C.M. et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202, 1171–1177 (2005).

    Article  CAS  Google Scholar 

  5. Chen, C.J. et al. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat. Med. 13, 851–856 (2007).

    Article  CAS  Google Scholar 

  6. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).

    Article  CAS  Google Scholar 

  7. Fritz, J.H., Ferrero, R.L., Philpott, D.J. & Girardin, S.E. Nod-like proteins in immunity, inflammation and disease. Nat. Immunol. 7, 1250–1257 (2006).

    Article  CAS  Google Scholar 

  8. Medzhitov, R. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1, 135–145 (2001).

    Article  CAS  Google Scholar 

  9. Beutler, B. et al. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu. Rev. Immunol. 24, 353–389 (2006).

    Article  CAS  Google Scholar 

  10. Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 8, 59–73 (2008).

    Article  CAS  Google Scholar 

  11. Obeid, M. et al. Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis. Cell Death Differ. 14, 1848–1850 (2007).

    Article  CAS  Google Scholar 

  12. Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    Article  CAS  Google Scholar 

  13. Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).

    Article  CAS  Google Scholar 

  14. Lotze, M.T. et al. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol. Rev. 220, 60–81 (2007).

    Article  CAS  Google Scholar 

  15. Apetoh, L. et al. Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007).

    Article  CAS  Google Scholar 

  16. Sancho, D. et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458, 899–903 (2009).

    Article  CAS  Google Scholar 

  17. Martinon, F. & Tschopp, J. Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ. 14, 10–22 (2007).

    Article  CAS  Google Scholar 

  18. Di Virgilio, F. Liaisons dangereuses: P2X7 and the inflammasome. Trends Pharmacol. Sci. 28, 465–472 (2007).

    Article  CAS  Google Scholar 

  19. Eisenbarth, S.C., Colegio, O.R., O'Connor, W., Sutterwala, F.S. & Flavell, R.A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Poyet, J.L. et al. Identification of Ipaf, a human caspase-1–activating protein related to Apaf-1. J. Biol. Chem. 276, 28309–28313 (2001).

    Article  CAS  Google Scholar 

  22. Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002).

    Article  CAS  Google Scholar 

  23. Sutterwala, F.S. et al. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24, 317–327 (2006).

    Article  CAS  Google Scholar 

  24. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. 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 

  27. Kanneganti, T.D. et al. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J. Biol. Chem. 281, 36560–36568 (2006).

    Article  CAS  Google Scholar 

  28. 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 

  29. Ogura, Y., Sutterwala, F.S. & Flavell, R.A. The inflammasome: first line of the immune response to cell stress. Cell 126, 659–662 (2006).

    Article  CAS  Google Scholar 

  30. Dinarello, C.A. Interleukin-1β, interleukin-18, and the interleukin-1β converting enzyme. Ann. NY Acad. Sci. 856, 1–11 (1998).

    Article  CAS  Google Scholar 

  31. Brydges, S. & Kastner, D.L. The systemic autoinflammatory diseases: inborn errors of the innate immune system. Curr. Top. Microbiol. Immunol. 305, 127–160 (2006).

    CAS  PubMed  Google Scholar 

  32. Reginato, A.M. & Olsen, B.R. Genetics and experimental models of crystal-induced arthritis. Lessons learned from mice and men: is it crystal clear? Curr. Opin. Rheumatol. 19, 134–145 (2007).

    Article  CAS  Google Scholar 

  33. McIntyre, K.W. et al. Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti–IL-1 receptor monoclonal antibody. J. Exp. Med. 173, 931–939 (1991).

    Article  CAS  Google Scholar 

  34. Selzner, N. et al. Water induces autocrine stimulation of tumor cell killing through ATP release and P2 receptor binding. Cell Death Differ. 11 (Suppl 2), S172–S180 (2004).

    Article  CAS  Google Scholar 

  35. Solle, M. et al. Altered cytokine production in mice lacking P2X7 receptors. J. Biol. Chem. 276, 125–132 (2001).

    Article  CAS  Google Scholar 

  36. Srinivasula, S.M. et al. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J. Biol. Chem. 277, 21119–21122 (2002).

    Article  CAS  Google Scholar 

  37. Koebel, C.M. et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450, 903–907 (2007).

    Article  CAS  Google Scholar 

  38. Gu, B.J. et al. A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor. J. Biol. Chem. 276, 11135–11142 (2001).

    Article  CAS  Google Scholar 

  39. Sluyter, R., Shemon, A.N. & Wiley, J.S. Glu496 to Ala polymorphism in the P2X7 receptor impairs ATP-induced IL-1β release from human monocytes. J. Immunol. 172, 3399–3405 (2004).

    Article  CAS  Google Scholar 

  40. Bours, M.J., Swennen, E.L., Di Virgilio, F., Cronstein, B.N. & Dagnelie, P.C. Adenosine 5′-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol. Ther. 112, 358–404 (2006).

    Article  CAS  Google Scholar 

  41. Blankenstein, T. The role of tumor stroma in the interaction between tumor and immune system. Curr. Opin. Immunol. 17, 180–186 (2005).

    Article  CAS  Google Scholar 

  42. Hinrichs, C.S., Gattinoni, L. & Restifo, N.P. Programming CD8+ T cells for effective immunotherapy. Curr. Opin. Immunol. 18, 363–370 (2006).

    Article  CAS  Google Scholar 

  43. Ferrari, D., Chiozzi, P., Falzoni, S., Hanau, S. & Di Virgilio, F. Purinergic modulation of interleukin-1β release from microglial cells stimulated with bacterial endotoxin. J. Exp. Med. 185, 579–582 (1997).

    Article  CAS  Google Scholar 

  44. Adachi, O. et al. Targeted disruption of the Myd88 gene results in loss of IL-1– and IL-18–mediated function. Immunity 9, 143–150 (1998).

    Article  CAS  Google Scholar 

  45. Franchi, L., Kanneganti, T.D., Dubyak, G.R. & Nunez, G. Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria. J. Biol. Chem. 282, 18810–18818 (2007).

    Article  CAS  Google Scholar 

  46. Muruve, D.A. et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452, 103–107 (2008).

    Article  CAS  Google Scholar 

  47. Pétrilli, V., Dostert, C., Muruve, D.A. & Tschopp, J. The inflammasome: a danger sensing complex triggering innate immunity. Curr. Opin. Immunol. 19, 615–622 (2007).

    Article  Google Scholar 

  48. Krelin, Y. et al. Interleukin-1β–driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors. Cancer Res. 67, 1062–1071 (2007).

    Article  CAS  Google Scholar 

  49. Hagemann, T., Balkwill, F. & Lawrence, T. Inflammation and cancer: a double-edged sword. Cancer Cell 12, 300–301 (2007).

    Article  CAS  Google Scholar 

  50. Greten, F.R. et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).

    Article  CAS  Google Scholar 

  51. Naugler, W.E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121–124 (2007).

    Article  CAS  Google Scholar 

  52. Balkwill, F., Charles, K.A. & Mantovani, A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7, 211–217 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank I. Couillin (CNRS) and A. Mignon (Cochin Hospital) for helpful discussion and for providing IL-1RA, R. Schreiber (Washington University School of Medicine) for monoclonal antibodies to IL-1α, IL-1β and IL-1R, H. Yang (Feinstein Institute for Medical Research) for antibody to HMGB1, H. Yagita (School of Medicine, Juntendo University) for the N2B2 antibody to mouse TRAIL, J.-C. Guéry (INSERM) for IL12rb2−/− mice, V. Dixit (Pennington Biomedical Research Center) for Pycard−/− mice, M. Albert (Pasteur Institute) for membrane-bound OVA–transfected mouse embryonic fibroblast cells, S. Forget and J. Bombled for access to the genomics platform, V. Vasseur and the Institut Gustave Roussy animal facility for breeding of transgenic mice, I. Martins for help in ATP release screening and A. Boissonnas (INSERM, Curie Institute) for providing OT1-GFP mice. We are deeply indebted to P. Arveux and S. Dabakuyo for useful help with the statistical analyses. The authors are supported by grants from the Ligue Nationale contre le Cancer (to L. Aymeric., G.K. and L.Z.), the Fondation pour la Recherche Médicale (to L. Apetoh., G.K., E.U., F.S. and L.Z.), the European Union (INFLACARE grant), the association for International cancer research (to G.K.) Cancéropôle Ile-de-France, Institut National du Cancer (L.Z., G.K.), Agence Nationale pour la Recherche (to G.K.), the European Molecular Biology Organization (L. Apetoh.), INSERM (A.T.), the National Health, Association pour la recherche sur le cancer RC (to G.M.), National Health and Medical Research Council of Australia, Cancer Council of Victoria, the China Scholarship Council (Y.M.) and the Leukemia Foundation (M.J.S., N.M.M. and N.M.H.). K.V. is the recipient of a European Respiratory Society Fellowship (number 605).

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Author notes

  1. François Ghiringhelli, Lionel Apetoh, Antoine Tesniere, Laetitia Aymeric, Mark J Smyth, Guido Kroemer and Laurence Zitvogel: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM), U805, Villejuif, France

    François Ghiringhelli, Lionel Apetoh, Laetitia Aymeric, Yuting Ma, Carla Ortiz, Karim Vermaelen, Grégoire Mignot, Evelyn Ullrich, Fabrice André & Laurence Zitvogel

  2. Institut Gustave Roussy, Villejuif, France

    François Ghiringhelli, Lionel Apetoh, Antoine Tesniere, Laetitia Aymeric, Yuting Ma, Carla Ortiz, Karim Vermaelen, Theocharis Panaretakis, Evelyn Ullrich, Jean-Luc Perfettini, Frédéric Schlemmer, Ezgi Tasdemir, Fabrice André, Guido Kroemer & Laurence Zitvogel

  3. AVENIR team INSERM CRI-866, Dijon, France

    François Ghiringhelli

  4. Centre Georges Francois Leclerc, Dijon, France

    François Ghiringhelli & Grégoire Mignot

  5. Université Paris-Sud, Villejuif, France

    Lionel Apetoh, Antoine Tesniere, Laetitia Aymeric, Yuting Ma, Carla Ortiz, Karim Vermaelen, Theocharis Panaretakis, Evelyn Ullrich, Jean-Luc Perfettini, Frédéric Schlemmer, Ezgi Tasdemir, Fabrice André, Guido Kroemer & Laurence Zitvogel

  6. Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Lionel Apetoh

  7. INSERM, U848, Villejuif, France

    Antoine Tesniere, Theocharis Panaretakis, Jean-Luc Perfettini, Frédéric Schlemmer, Ezgi Tasdemir & Guido Kroemer

  8. Universidad de Chile, Facultad de Ciencias Químicas Farmacéuticas, Centro FONDAP Estudios Moleculares de la Célula, Santiago, Chile

    Carla Ortiz

  9. Department of Respiratory Medicine, Laboratory of Immunoregulation, Ghent University Hospital, Belgium

    Karim Vermaelen

  10. INSERM, U818, Institut Pasteur, Paris, France

    Martin Uhl

  11. UPR 2228-CNRS, Laboratoire de Régulation Transcriptionnelle et Maladies Génétiques, Biomédicale des Saints-Pères, Université Paris Descartes, Paris Cedex 06, France

    Pierre Génin & Ahmet Civas

  12. UMR6218, IEM, CNRS Transgenose Institute, Orleans, France

    Bernhard Ryffel

  13. UMR8619, CNRS, Université Paris, Orsay, France

    Jean Kanellopoulos

  14. Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

    Jürg Tschopp

  15. Centre René Huguenin, INSERM U735, St. Cloud, France

    Rosette Lidereau

  16. Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

    Nicole M McLaughlin, Nicole M Haynes & Mark J Smyth

  17. CICBT507, Villejuif, France

    Laurence Zitvogel

Authors

  1. François Ghiringhelli

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  2. Lionel Apetoh

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  3. Antoine Tesniere

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  4. Laetitia Aymeric

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  5. Yuting Ma

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  6. Carla Ortiz

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  7. Karim Vermaelen

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  8. Theocharis Panaretakis

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  9. Grégoire Mignot

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  10. Evelyn Ullrich

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  11. Jean-Luc Perfettini

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  12. Frédéric Schlemmer

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  13. Ezgi Tasdemir

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  14. Martin Uhl

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  15. Pierre Génin

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  16. Ahmet Civas

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  17. Bernhard Ryffel

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  18. Jean Kanellopoulos

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  19. Jürg Tschopp

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  20. Fabrice André

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  21. Rosette Lidereau

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  22. Nicole M McLaughlin

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  23. Nicole M Haynes

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  24. Mark J Smyth

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  25. Guido Kroemer

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  26. Laurence Zitvogel

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Contributions

F.G., L. Aymeric., A.T., L. Apetoh., T.P., F.S., G.M., E.U., Y.M., N.M.M., N.M.H. and M.J.S. performed in vitro and in vivo experiments. C.O., E.T., P.G. and A.C. performed in vitro experiments. A.T. and T.P. performed immunofluorescence experiments. M.U., J.-L.P., B.R., J.K. and J.T. provided transgenic cells or mice and gave scientific advice. K.V., F.A., R.L., F.G. and A.T. performed the single nucleotide polymorphism analysis on cohorts of subjects with cancer. F.G., L. Apetoh., M.J.S. and A.T. prepared the figures and drafted the manuscript. G.K. and L.Z. designed the study and wrote the manuscript. M.J.S., G.K. and L.Z. all contributed equally to the design of the experiments and to the writing of the manuscript.

Corresponding authors

Correspondence to Guido Kroemer or Laurence Zitvogel.

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Ghiringhelli, F., Apetoh, L., Tesniere, A. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors. Nat Med 15, 1170–1178 (2009). https://doi.org/10.1038/nm.2028

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  • Received: 16 July 2009

  • Accepted: 18 August 2009

  • Published: 20 September 2009

  • Issue Date: October 2009

  • DOI: https://doi.org/10.1038/nm.2028