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PMID: 18604214 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization.

Nature immunology ·Vol. 9 ·No. 8 ·2008-08-00 ·Pages 847-56

Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E

Abstract

Inhalation of silica crystals causes inflammation in the alveolar space. Prolonged exposure to silica can lead to the development of silicosis, an irreversible, fibrotic pulmonary disease. The mechanisms by which silica and other crystals activate immune cells are not well understood. Here we demonstrate that silica and aluminum salt crystals activated inflammasomes formed by the cytoplasmic receptor NALP3. NALP3 activation required phagocytosis of crystals, and this uptake subsequently led to lysosomal damage and rupture. 'Sterile' lysosomal damage (without crystals) also induced NALP3 activation, and inhibition of either phagosomal acidification or cathepsin B activity impaired NALP3 activation. Our results indicate that the NALP3 inflammasome senses lysosomal damage as an endogenous 'danger' signal.

MeSH Terms
Aluminum Compounds/metabolism Animals Carrier Proteins Inflammation/chemically induced,immunology,metabolism,pathology Inflammation Mediators/physiology Macrophages/drug effects,enzymology,metabolism Mice Mice, Inbred C57BL NLR Family, Pyrin Domain-Containing 3 Protein Silicon Dioxide/metabolism Silicosis/immunology,pathology
Chemicals
Aluminum Compounds Carrier Proteins Inflammation Mediators NLR Family, Pyrin Domain-Containing 3 Protein NLRP3 protein, human Silicon Dioxide
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Hornung Veit
Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Bauernfeind Franz
Halle Annett
Samstad Eivind O
Kono Hajime
Rock Kenneth L
Fitzgerald Katherine A
Latz Eicke
References (39)
39 references, click to expand
  1. Pannexin-1 couples to maitotoxin- and nigericin-induced interleukin-1beta release through a dye uptake-independent pathway.
    J Biol Chem. 2007 Jan 26;282(4):2386-94 PMID: 17121814
  2. Toll-like receptors.
    Annu Rev Immunol. 2003;21:335-76 PMID: 12524386
  3. Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis.
    Science. 2008 Feb 1;319(5863):624-7 PMID: 18239127
  4. Cryopyrin activates the inflammasome in response to toxins and ATP.
    Nature. 2006 Mar 9;440(7081):228-32 PMID: 16407890
  5. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf.
    Nature. 2004 Jul 8;430(6996):213-8 PMID: 15190255
  6. Dectin-1 is a major beta-glucan receptor on macrophages.
    J Exp Med. 2002 Aug 5;196(3):407-12 PMID: 12163569
  7. Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC.
    Cell Host Microbe. 2007 Sep 13;2(3):147-59 PMID: 18005730
  8. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder.
    Immunity. 2004 Mar;20(3):319-25 PMID: 15030775
  9. Mechanism of L-leucyl-L-leucine methyl ester-mediated killing of cytotoxic lymphocytes: dependence on a lysosomal thiol protease, dipeptidyl peptidase I, that is enriched in these cells.
    Proc Natl Acad Sci U S A. 1990 Jan;87(1):83-7 PMID: 2296607
  10. The inflammasome: a danger sensing complex triggering innate immunity.
    Curr Opin Immunol. 2007 Dec;19(6):615-22 PMID: 17977705
  11. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages.
    Nat Immunol. 2006 Jun;7(6):576-82 PMID: 16648852
  12. Toll-like receptor-dependent and -independent viperin gene expression and counter-regulation by PRDI-binding factor-1/BLIMP1.
    J Biol Chem. 2006 Sep 8;281(36):26188-95 PMID: 16849320
  13. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling.
    Immunity. 2007 Apr;26(4):433-43 PMID: 17433728
  14. CA074 methyl ester: a proinhibitor for intracellular cathepsin B.
    Arch Biochem Biophys. 1992 Dec;299(2):377-80 PMID: 1444478
  15. Monosodium urate monohydrate crystal-induced inflammation in vivo: quantitative histomorphometric analysis of cellular events.
    Arthritis Rheum. 2002 Jun;46(6):1643-50 PMID: 12115197
  16. Mechanisms in the pathogenesis of asbestosis and silicosis.
    Am J Respir Crit Care Med. 1998 May;157(5 Pt 1):1666-80 PMID: 9603153
  17. Immortalization of cloned mouse splenic macrophages with a retrovirus containing the v-raf/mil and v-myc oncogenes.
    Cell Immunol. 1988 Oct 15;116(2):341-51 PMID: 2460250
  18. 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
  19. Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells.
    J Exp Med. 2008 Apr 14;205(4):869-82 PMID: 18362170
  20. Gout-associated uric acid crystals activate the NALP3 inflammasome.
    Nature. 2006 Mar 9;440(7081):237-41 PMID: 16407889
  21. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3.
    Nature. 2006 Mar 9;440(7081):233-6 PMID: 16407888
  22. Disease-associated mutations in CIAS1 induce cathepsin B-dependent rapid cell death of human THP-1 monocytic cells.
    Blood. 2007 Apr 1;109(7):2903-11 PMID: 17164343
  23. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors.
    Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13766-71 PMID: 11095740
  24. Critical role for cathepsin B in mediating caspase-1-dependent interleukin-18 maturation and caspase-1-independent necrosis triggered by the microbial toxin nigericin.
    Cell Death Differ. 2003 Sep;10(9):956-68 PMID: 12934070
  25. Regulation of cellular function by products of lysosomal enzyme activity: elimination of human natural killer cells by a dipeptide methyl ester generated from L-leucine methyl ester by monocytes or polymorphonuclear leukocytes.
    Proc Natl Acad Sci U S A. 1985 Apr;82(8):2468-72 PMID: 3857595
  26. Intracellular K(+) inhibits apoptosis by suppressing the Apaf-1 apoptosome formation and subsequent downstream pathways but not cytochrome c release.
    Cell Death Differ. 2007 Dec;14(12):2068-75 PMID: 17885667
  27. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis.
    Free Radic Biol Med. 2003 Jun 15;34(12):1507-16 PMID: 12788471
  28. New developments in the understanding of immunology in silicosis.
    Curr Opin Allergy Clin Immunol. 2007 Apr;7(2):168-73 PMID: 17351471
  29. Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2.
    J Immunol. 2008 Mar 15;180(6):4050-7 PMID: 18322214
  30. TLR9 signals after translocating from the ER to CpG DNA in the lysosome.
    Nat Immunol. 2004 Feb;5(2):190-8 PMID: 14716310
  31. Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor.
    EMBO J. 2006 Nov 1;25(21):5071-82 PMID: 17036048
  32. Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production.
    Nat Genet. 1995 Feb;9(2):202-9 PMID: 7719350
  33. The Apaf-1 apoptosome: a large caspase-activating complex.
    Biochimie. 2002 Feb-Mar;84(2-3):203-14 PMID: 12022951
  34. Aluminum hydroxide adjuvants activate caspase-1 and induce IL-1beta and IL-18 release.
    J Immunol. 2007 Apr 15;178(8):5271-6 PMID: 17404311
  35. Ligand-induced conformational changes allosterically activate Toll-like receptor 9.
    Nat Immunol. 2007 Jul;8(7):772-9 PMID: 17572678
  36. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response.
    Nature. 2008 Mar 6;452(7183):103-7 PMID: 18288107
  37. 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
  38. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica.
    Science. 2008 May 2;320(5876):674-7 PMID: 18403674
  39. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration.
    Cell Death Differ. 2007 Sep;14(9):1583-9 PMID: 17599094
Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.1631
Published
2008-08-00
Epub
2008-00-11
Pages
847-56
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC2834784
Subset
IM
Grants
NIAID NIH HHS · R01 AI083713 · United States
NIAID NIH HHS · R01 AI043543 · United States
NIAID NIH HHS · R01 AI-065483 · United States
NIAID NIH HHS · R01 AI065483 · United States
NIAID NIH HHS · R01 AI067497-03 · United States
NIAID NIH HHS · R01 AI065483-01 · United States
NIAID NIH HHS · R01 AI043543-01A1 · United States
NIAID NIH HHS · R01 AI083713-02 · United States
NIAID NIH HHS · R01 AI067497 · United States
NIAID NIH HHS · R01 AI-067497 · United States
Corrections
CommentIn
PMID: 18645588
External Links
PubMed source DOI: 10.1038/ni.1631 PMC Full Text View journal details
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