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PMID: 19767732 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors.

Nature medicine ·Vol. 15 ·No. 10 ·2009-10-00 ·Pages 1170-8

Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, Vermaelen K, Panaretakis T, Mignot G, Ullrich E, Perfettini JL, Schlemmer F, Tasdemir E, Uhl M, Génin P, Civas A, Ryffel B, Kanellopoulos J, Tschopp J, André F, Lidereau R, McLaughlin NM, Haynes NM, Smyth MJ, Kroemer G, Zitvogel L

Abstract

The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-gamma (IFN-gamma)-producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X(7) purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1beta (IL-1beta). The priming of IFN-gamma-producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3(-/-)) or caspase-1-deficient (Casp-1(-/-)) mice unless exogenous IL-1beta is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7(-/-) or Nlrp3(-/-) or Casp1(-/-) hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells.

MeSH Terms
Animals Carrier Proteins/immunology,metabolism Caspase 1/metabolism Dendritic Cells/cytology,immunology,metabolism Immunity/immunology Immunity, Innate Inflammation/immunology Interleukin-1beta/metabolism Mice Mice, Knockout NLR Family, Pyrin Domain-Containing 3 Protein Thymoma/immunology
Chemicals
Carrier Proteins Interleukin-1beta NLR Family, Pyrin Domain-Containing 3 Protein Nlrp3 protein, mouse Caspase 1
Authors & Affiliations
26 authors, click to expand affiliations / ORCID
Ghiringhelli François
Institut National de la Santé et de la Recherche Médicale, U805, Villejuif, France.
Apetoh Lionel
Tesniere Antoine
Aymeric Laetitia
Ma Yuting
Ortiz Carla
Vermaelen Karim
Panaretakis Theocharis
Mignot Grégoire
Ullrich Evelyn
Perfettini Jean-Luc
Schlemmer Frédéric
Tasdemir Ezgi
Uhl Martin
Génin Pierre
Civas Ahmet
Ryffel Bernhard
Kanellopoulos Jean
Tschopp Jürg
André Fabrice
Lidereau Rosette
McLaughlin Nicole M
Haynes Nicole M
Smyth Mark J
Kroemer Guido
Zitvogel Laurence
References (52)
52 references, click to expand
  1. Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria.
    J Biol Chem. 2007 Jun 29;282(26):18810-8 PMID: 17491021
  2. Dendritic cells and the control of immunity.
    Nature. 1998 Mar 19;392(6673):245-52 PMID: 9521319
  3. Toll-like receptors and innate immunity.
    Nat Rev Immunol. 2001 Nov;1(2):135-45 PMID: 11905821
  4. The P2X7 receptor: a key player in IL-1 processing and release.
    J Immunol. 2006 Apr 1;176(7):3877-83 PMID: 16547218
  5. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3.
    Nature. 2006 Mar 9;440(7081):233-6 PMID: 16407888
  6. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1.
    Immunity. 2006 Mar;24(3):317-27 PMID: 16546100
  7. The danger model: a renewed sense of self.
    Science. 2002 Apr 12;296(5566):301-5 PMID: 11951032
  8. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants.
    Nature. 2008 Jun 19;453(7198):1122-6 PMID: 18496530
  9. Purinergic modulation of interleukin-1 beta release from microglial cells stimulated with bacterial endotoxin.
    J Exp Med. 1997 Feb 3;185(3):579-82 PMID: 9053458
  10. A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor.
    J Biol Chem. 2001 Apr 6;276(14):11135-42 PMID: 11150303
  11. A blast from the past: clearance of apoptotic cells regulates immune responses.
    Nat Rev Immunol. 2002 Dec;2(12):965-75 PMID: 12461569
  12. Smoldering and polarized inflammation in the initiation and promotion of malignant disease.
    Cancer Cell. 2005 Mar;7(3):211-7 PMID: 15766659
  13. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.
    Mol Cell. 2002 Aug;10(2):417-26 PMID: 12191486
  14. The systemic autoinflammatory diseases: inborn errors of the innate immune system.
    Curr Top Microbiol Immunol. 2006;305:127-60 PMID: 16724804
  15. Water induces autocrine stimulation of tumor cell killing through ATP release and P2 receptor binding.
    Cell Death Differ. 2004 Dec;11 Suppl 2:S172-80 PMID: 15459753
  16. Inflammation and cancer: a double-edged sword.
    Cancer Cell. 2007 Oct;12(4):300-1 PMID: 17936555
  17. Immunological aspects of cancer chemotherapy.
    Nat Rev Immunol. 2008 Jan;8(1):59-73 PMID: 18097448
  18. Calreticulin exposure dictates the immunogenicity of cancer cell death.
    Nat Med. 2007 Jan;13(1):54-61 PMID: 17187072
  19. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.
    Cell. 2004 Aug 6;118(3):285-96 PMID: 15294155
  20. Adaptive immunity maintains occult cancer in an equilibrium state.
    Nature. 2007 Dec 6;450(7171):903-7 PMID: 18026089
  21. Glu496 to Ala polymorphism in the P2X7 receptor impairs ATP-induced IL-1 beta release from human monocytes.
    J Immunol. 2004 Mar 15;172(6):3399-405 PMID: 15004138
  22. Gout-associated uric acid crystals activate the NALP3 inflammasome.
    Nature. 2006 Mar 9;440(7081):237-41 PMID: 16407889
  23. Interleukin-1beta-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors.
    Cancer Res. 2007 Feb 1;67(3):1062-71 PMID: 17283139
  24. Altered cytokine production in mice lacking P2X(7) receptors.
    J Biol Chem. 2001 Jan 5;276(1):125-32 PMID: 11016935
  25. Cryopyrin activates the inflammasome in response to toxins and ATP.
    Nature. 2006 Mar 9;440(7081):228-32 PMID: 16407890
  26. Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1.
    J Biol Chem. 2001 Jul 27;276(30):28309-13 PMID: 11390368
  27. Liaisons dangereuses: P2X(7) and the inflammasome.
    Trends Pharmacol Sci. 2007 Sep;28(9):465-72 PMID: 17692395
  28. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large.
    Annu Rev Immunol. 2006;24:353-89 PMID: 16551253
  29. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1.
    J Biol Chem. 2002 Jun 14;277(24):21119-22 PMID: 11967258
  30. Genetics and experimental models of crystal-induced arthritis. Lessons learned from mice and men: is it crystal clear?
    Curr Opin Rheumatol. 2007 Mar;19(2):134-45 PMID: 17278928
  31. 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. 1991 Apr 1;173(4):931-9 PMID: 1826128
  32. Pathogen recognition and innate immunity.
    Cell. 2006 Feb 24;124(4):783-801 PMID: 16497588
  33. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.
    Nat Med. 2007 Sep;13(9):1050-9 PMID: 17704786
  34. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function.
    Immunity. 1998 Jul;9(1):143-50 PMID: 9697844
  35. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity.
    Nature. 2009 Apr 16;458(7240):899-903 PMID: 19219027
  36. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder.
    Immunity. 2004 Mar;20(3):319-25 PMID: 15030775
  37. Inflammatory caspases and inflammasomes: master switches of inflammation.
    Cell Death Differ. 2007 Jan;14(1):10-22 PMID: 16977329
  38. Adenosine 5'-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation.
    Pharmacol Ther. 2006 Nov;112(2):358-404 PMID: 16784779
  39. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells.
    Nat Med. 2007 Jul;13(7):851-6 PMID: 17572686
  40. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors.
    Nature. 2002 Apr 11;416(6881):603-7 PMID: 11948342
  41. The role of tumor stroma in the interaction between tumor and immune system.
    Curr Opin Immunol. 2005 Apr;17(2):180-6 PMID: 15766679
  42. The inflammasome: first line of the immune response to cell stress.
    Cell. 2006 Aug 25;126(4):659-62 PMID: 16923387
  43. The inflammasome: a danger sensing complex triggering innate immunity.
    Curr Opin Immunol. 2007 Dec;19(6):615-22 PMID: 17977705
  44. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA.
    J Biol Chem. 2006 Dec 1;281(48):36560-8 PMID: 17008311
  45. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement.
    J Exp Med. 2005 Nov 7;202(9):1171-7 PMID: 16260486
  46. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response.
    Nature. 2008 Mar 6;452(7183):103-7 PMID: 18288107
  47. Interleukin-1 beta, interleukin-18, and the interleukin-1 beta converting enzyme.
    Ann N Y Acad Sci. 1998 Sep 29;856:1-11 PMID: 9917859
  48. Nod-like proteins in immunity, inflammation and disease.
    Nat Immunol. 2006 Dec;7(12):1250-7 PMID: 17110941
  49. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity.
    Immunol Rev. 2007 Dec;220:60-81 PMID: 17979840
  50. Programming CD8+ T cells for effective immunotherapy.
    Curr Opin Immunol. 2006 Jun;18(3):363-70 PMID: 16616471
  51. Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis.
    Cell Death Differ. 2007 Oct;14(10):1848-50 PMID: 17657249
  52. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production.
    Science. 2007 Jul 6;317(5834):121-4 PMID: 17615358
Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.2028
Published
2009-10-00
Epub
2009-00-20
Pages
1170-8
Language
English
Region
United States
NLM ID
9502015
Subset
IM
Corrections
CommentIn
PMID: 22395693
External Links
PubMed source DOI: 10.1038/nm.2028 View journal details
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