Home LiteratureArticle Details
PMID: 20872834 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

NLRP3 inflammasome plays a key role in the regulation of intestinal homeostasis.

Inflammatory bowel diseases ·Vol. 17 ·No. 6 ·2011-06-00 ·Pages 1359-72

Hirota SA, Ng J, Lueng A, Khajah M, Parhar K, Li Y, Lam V, Potentier MS, Ng K, Bawa M, McCafferty DM, Rioux KP, Ghosh S, Xavier RJ, Colgan SP, Tschopp J, Muruve D, MacDonald JA, Beck PL

Abstract

Attenuated innate immune responses to the intestinal microbiota have been linked to the pathogenesis of Crohn's disease (CD). Recent genetic studies have revealed that hypofunctional mutations of NLRP3, a member of the NOD-like receptor (NLR) superfamily, are associated with an increased risk of developing CD. NLRP3 is a key component of the inflammasome, an intracellular danger sensor of the innate immune system. When activated, the inflammasome triggers caspase-1-dependent processing of inflammatory mediators, such as IL-1β and IL-18. In the current study we sought to assess the role of the NLRP3 inflammasome in the maintenance of intestinal homeostasis through its regulation of innate protective processes. To investigate this role, Nlrp3(-/-) and wildtype mice were assessed in the dextran sulfate sodium and 2,4,6-trinitrobenzenesulfonic acid models of experimental colitis. Nlrp3(-/-) mice were found to be more susceptible to experimental colitis, an observation that was associated with reduced IL-1β, reduced antiinflammatory cytokine IL-10, and reduced protective growth factor TGF-β. Macrophages isolated from Nlrp3(-/-) mice failed to respond to bacterial muramyl dipeptide. Furthermore, Nlrp3-deficient neutrophils exhibited reduced chemotaxis and enhanced spontaneous apoptosis, but no change in oxidative burst. Lastly, Nlrp3(-/-) mice displayed altered colonic β-defensin expression, reduced colonic antimicrobial secretions, and a unique intestinal microbiota. Our data confirm an essential role for the NLRP3 inflammasome in the regulation of intestinal homeostasis and provide biological insight into disease mechanisms associated with increased risk of CD in individuals with NLRP3 mutations.

MeSH Terms
Animals Apoptosis/physiology Carrier Proteins/physiology Chemotaxis/physiology Colitis/physiopathology Disease Models, Animal Furans Homeostasis/physiology Immunity, Innate/physiology Inflammasomes/physiology Interleukin-10/physiology Interleukin-1beta/physiology Intestines/physiology Mice NLR Family, Pyrin Domain-Containing 3 Protein Thiophenes Transforming Growth Factor beta/physiology
Chemicals
3,4-bis-(2,4,5-trimethyl-thiophen-3-yl)furan-2,5-dione Carrier Proteins Furans Inflammasomes Interleukin-1beta NLR Family, Pyrin Domain-Containing 3 Protein Nlrp3 protein, mouse Thiophenes Transforming Growth Factor beta Interleukin-10
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Hirota Simon A
Gastrointestinal Research Group, University of Calgary, Calgary, AB, Canada. [email protected]
Ng Jeffrey
Lueng Alan
Khajah Maitham
Parhar Ken
Li Yan
Lam Victor
Potentier Mireille S
Ng Kelvin
Bawa Misha
McCafferty Donna-Marie
Rioux Kevin P
Ghosh Subrata
Xavier Ramnik J
Colgan Sean P
Tschopp Jurg
Muruve Daniel
MacDonald Justin A
Beck Paul L
References (69)
69 references, click to expand
  1. Reduced alpha-defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn's disease.
    Gut. 2008 Jul;57(7):903-10 PMID: 18305068
  2. Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis.
    J Clin Invest. 2008 Feb;118(2):545-59 PMID: 18188453
  3. Paradoxical roles of different nitric oxide synthase isoforms in colonic injury.
    Am J Physiol Gastrointest Liver Physiol. 2004 Jan;286(1):G137-47 PMID: 14665440
  4. Twin studies reveal specific imbalances in the mucosa-associated microbiota of patients with ileal Crohn's disease.
    Inflamm Bowel Dis. 2009 May;15(5):653-60 PMID: 19023901
  5. Common variants in the NLRP3 region contribute to Crohn's disease susceptibility.
    Nat Genet. 2009 Jan;41(1):71-6 PMID: 19098911
  6. Immunosuppressive and anti-inflammatory properties of interleukin 10.
    Ann Med. 1995 Oct;27(5):537-41 PMID: 8541028
  7. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface.
    Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20858-63 PMID: 19075245
  8. Activation of toll-like receptor 3 protects against DSS-induced acute colitis.
    Inflamm Bowel Dis. 2007 Jul;13(7):856-64 PMID: 17393379
  9. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization.
    Nat Immunol. 2008 Aug;9(8):847-56 PMID: 18604214
  10. Phagocyte dysfunction and inflammatory bowel disease.
    Inflamm Bowel Dis. 2008 Oct;14(10):1443-52 PMID: 18421761
  11. Inhibition of alveolar neutrophil immigration in endotoxemia is macrophage inflammatory protein 2 independent.
    J Surg Res. 2000 May 1;90(1):51-7 PMID: 10781375
  12. The myeloid differentiation factor 88 (MyD88) is required for CD4+ T cell effector function in a murine model of inflammatory bowel disease.
    J Immunol. 2008 Feb 1;180(3):1886-94 PMID: 18209086
  13. Fecal beta-defensin-2 in children with inflammatory bowel diseases.
    J Pediatr Gastroenterol Nutr. 2009 Jan;48(1):117-20 PMID: 19172136
  14. Nod2 is required for the regulation of commensal microbiota in the intestine.
    Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15813-8 PMID: 19805227
  15. Regulation of IL-8 and IL-1beta expression in Crohn's disease associated NOD2/CARD15 mutations.
    Hum Mol Genet. 2004 Aug 15;13(16):1715-25 PMID: 15198989
  16. Enhanced human beta-defensin-2 (hBD-2) expression by corticosteroids is independent of NF-kappaB in colonic epithelial cells (CaCo2).
    Dig Dis Sci. 2005 Jul;50(7):1252-9 PMID: 16047468
  17. Dextran sulfate sodium-induced colonic histopathology, but not altered epithelial ion transport, is reduced by inhibition of phosphodiesterase activity.
    Am J Pathol. 2000 Jun;156(6):2169-77 PMID: 10854237
  18. Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome.
    Gut. 2010 Sep;59(9):1192-9 PMID: 20442201
  19. Cryopyrin-associated periodic syndromes and autoinflammation.
    Clin Exp Dermatol. 2008 Jan;33(1):1-9 PMID: 17927785
  20. NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression.
    Gut. 2004 Nov;53(11):1658-64 PMID: 15479689
  21. Human beta-defensin 2 but not beta-defensin 1 is expressed preferentially in colonic mucosa of inflammatory bowel disease.
    Eur J Gastroenterol Hepatol. 2002 Jul;14(7):745-52 PMID: 12169983
  22. Dysregulation of human beta-defensin-2 protein in inflammatory bowel disease.
    PLoS One. 2009 Jul 20;4(7):e6285 PMID: 19617917
  23. Ribosomal DNA sequence analysis of mucosa-associated bacteria in Crohn's disease.
    Inflamm Bowel Dis. 2004 Nov;10(6):824-33 PMID: 15626901
  24. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3.
    Nature. 2006 Mar 9;440(7081):233-6 PMID: 16407888
  25. DNA isolation protocols affect the detection limit of PCR approaches of bacteria in samples from the human gastrointestinal tract.
    Syst Appl Microbiol. 2001 Nov;24(3):405-10 PMID: 11822677
  26. Caspase-1-deficient mice have delayed neutrophil apoptosis and a prolonged inflammatory response to lipopolysaccharide-induced acute lung injury.
    J Immunol. 2002 Dec 1;169(11):6401-7 PMID: 12444148
  27. Colitis-associated variant of TLR2 causes impaired mucosal repair because of TFF3 deficiency.
    Gastroenterology. 2009 Jul;137(1):209-20 PMID: 19303021
  28. Inflammasomes in inflammatory disorders: the role of TLRs and their interactions with NLRs.
    Semin Immunopathol. 2007 Sep;29(3):239-48 PMID: 17805544
  29. Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases.
    Immunity. 2010 Mar 26;32(3):367-78 PMID: 20226691
  30. NOD2/CARD15 genotype influences MDP-induced cytokine release and basal IL-12p40 levels in primary isolated peripheral blood monocytes.
    Inflamm Bowel Dis. 2008 Aug;14(8):1033-40 PMID: 18383179
  31. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy.
    Appl Environ Microbiol. 2007 Aug;73(16):5261-7 PMID: 17586664
  32. Pure Hemozoin is inflammatory in vivo and activates the NALP3 inflammasome via release of uric acid.
    J Immunol. 2009 Oct 15;183(8):5208-20 PMID: 19783673
  33. Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease.
    Lancet. 2005 May 21-27;365(9473):1794-6 PMID: 15910952
  34. Inducible and constitutive beta-defensins are differentially expressed in Crohn's disease and ulcerative colitis.
    Inflamm Bowel Dis. 2003 Jul;9(4):215-23 PMID: 12902844
  35. Detection of muramyl dipeptide-sensing pathway defects in patients with Crohn's disease.
    Inflamm Bowel Dis. 2006 Jul;12(7):598-605 PMID: 16804397
  36. Dysbiosis in inflammatory bowel disease.
    Gut. 2004 Jan;53(1):1-4 PMID: 14684564
  37. Unravelling the pathogenesis of inflammatory bowel disease.
    Nature. 2007 Jul 26;448(7152):427-34 PMID: 17653185
  38. Decreased Paneth cell defensin expression in ileal Crohn's disease is independent of inflammation, but linked to the NOD2 1007fs genotype.
    Gut. 2009 Jun;58(6):882-3; discussion 883-4 PMID: 19433600
  39. Neutrophil chemokines KC and macrophage-inflammatory protein-2 are newly synthesized by tissue macrophages using distinct TLR signaling pathways.
    J Immunol. 2008 Mar 15;180(6):4308-15 PMID: 18322244
  40. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome.
    J Cell Biol. 2009 Oct 5;187(1):61-70 PMID: 19805629
  41. Characterization of microbial diversity by determining terminal restriction fragment length polymorphisms of genes encoding 16S rRNA.
    Appl Environ Microbiol. 1997 Nov;63(11):4516-22 PMID: 9361437
  42. Combined polymorphisms in genes encoding the inflammasome components NALP3 and CARD8 confer susceptibility to Crohn's disease in Swedish men.
    Am J Gastroenterol. 2009 May;104(5):1180-8 PMID: 19319132
  43. Reduced sensitivity of inducible nitric oxide synthase-deficient mice to chronic colitis.
    Free Radic Biol Med. 2001 Jul 15;31(2):153-63 PMID: 11440827
  44. The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4.
    J Immunol. 2007 Sep 1;179(5):3109-18 PMID: 17709525
  45. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer.
    J Exp Med. 2010 May 10;207(5):1045-56 PMID: 20385749
  46. Chronic stimulation of Nod2 mediates tolerance to bacterial products.
    Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19440-5 PMID: 18032608
  47. Phenotype-genotype analysis of cryopyrin-associated periodic syndromes (CAPS): description of a rare non-exon 3 and a novel CIAS1 missense mutation.
    J Clin Immunol. 2008 Mar;28(2):134-8 PMID: 18080732
  48. Hapten-induced model of chronic inflammation and ulceration in the rat colon.
    Gastroenterology. 1989 Mar;96(3):795-803 PMID: 2914642
  49. Neutrophil chemotaxis in a patient with neonatal-onset multisystem inflammatory disease and Muckle-Wells syndrome.
    Ann Allergy Asthma Immunol. 2005 Oct;95(4):394-9 PMID: 16279571
  50. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
    Methods. 2001 Dec;25(4):402-8 PMID: 11846609
  51. Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function.
    Gastroenterology. 2007 Apr;132(4):1359-74 PMID: 17408640
  52. The inflammasome: a danger sensing complex triggering innate immunity.
    Curr Opin Immunol. 2007 Dec;19(6):615-22 PMID: 17977705
  53. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist.
    Lancet. 2004 Nov 13-19;364(9447):1779-85 PMID: 15541451
  54. Inducible nitric oxide synthase from bone marrow-derived cells plays a critical role in regulating colonic inflammation.
    Gastroenterology. 2007 May;132(5):1778-90 PMID: 17449036
  55. Blockade of TGF-beta accelerates mucosal destruction through epithelial cell apoptosis.
    Biochem Biophys Res Commun. 2007 Aug 3;359(3):406-12 PMID: 17560553
  56. Optimal storage conditions for preserving granulocyte viability as monitored by Annexin V binding in whole blood.
    J Immunol Methods. 1999 May 27;225(1-2):27-38 PMID: 10365779
  57. The in vitro production and characterization of neutrophils from embryonic stem cells.
    Blood. 2004 Feb 1;103(3):852-9 PMID: 14525782
  58. Defective acute inflammation in Crohn's disease: a clinical investigation.
    Lancet. 2006 Feb 25;367(9511):668-78 PMID: 16503465
  59. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis.
    Immunity. 2010 Mar 26;32(3):379-91 PMID: 20303296
  60. Defensins and cathelicidins in gastrointestinal infections.
    Curr Opin Gastroenterol. 2007 Jan;23(1):32-8 PMID: 17133082
  61. CXCR2 is critical for dsRNA-induced lung injury: relevance to viral lung infection.
    J Inflamm (Lond). 2005 May 28;2(1):4 PMID: 15921526
  62. NOD2 3020insC mutation and the pathogenesis of Crohn's disease: impaired IL-1beta production points to a loss-of-function phenotype.
    Neth J Med. 2005 Sep;63(8):305-8 PMID: 16186640
  63. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica.
    Science. 2008 May 2;320(5876):674-7 PMID: 18403674
  64. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration.
    Cell Death Differ. 2007 Sep;14(9):1583-9 PMID: 17599094
  65. Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria.
    Nat Immunol. 2000 Aug;1(2):113-8 PMID: 11248802
  66. beta-Defensin-3 and -4 in intestinal epithelial cells display increased mRNA expression in ulcerative colitis.
    Clin Exp Immunol. 2004 Aug;137(2):379-85 PMID: 15270856
  67. An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients.
    J Cell Biol. 2002 Oct 14;159(1):91-102 PMID: 12370241
  68. Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis.
    Am J Physiol Gastrointest Liver Physiol. 2005 May;288(5):G1055-65 PMID: 15826931
  69. Quantitative aspects of the production of superoxide radicals by phagocytizing human granulocytes.
    J Lab Clin Med. 1975 Feb;85(2):245-52 PMID: 163283
Article Info
Journal
Inflammatory bowel diseases
Abbr.
Inflamm Bowel Dis
ISSN
1536-4844
DOI
10.1002/ibd.21478
Email
[email protected]
Published
2011-06-00
Epub
2010-00-24
Pages
1359-72
Language
English
Region
England
NLM ID
9508162
PMCID
PMC3026862
Subset
IM
Grants
NIDDK NIH HHS · P30 DK040561 · United States
NIDDK NIH HHS · R01 DK060049 · United States
NIDCR NIH HHS · P01 DE013499-050003 · United States
CIHR · Canada
NIDDK NIH HHS · P30 DK040561-15 · United States
NIDCR NIH HHS · DE13499 · United States
NIDDK NIH HHS · R29 DK050189 · United States
NHLBI NIH HHS · HL60569 · United States
NIDDK NIH HHS · R01 DK064869 · United States
NIDDK NIH HHS · R01 DK050189-10 · United States
NHLBI NIH HHS · R01 HL060569 · United States
NIDDK NIH HHS · R01 DK050189 · United States
NHLBI NIH HHS · R01 HL060569-12 · United States
NIDCR NIH HHS · P01 DE013499 · United States
NIDDK NIH HHS · R37 DK050189 · United States
NIDDK NIH HHS · DK50189 · United States
External Links
PubMed source DOI: 10.1002/ibd.21478 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2