Trends in Immunology
Volume 32, Issue 4, April 2011, Pages 171-179
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Review
The Nlrp3 inflammasome: contributions to intestinal homeostasis

https://doi.org/10.1016/j.it.2011.02.002Get rights and content

Inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis constitute a major health problem in developed countries. Moreover, IBD predisposes to the development of colorectal cancer. The intracellular NOD-like receptor Nlrp3 is rapidly emerging as a crucial regulator of intestinal homeostasis. This innate immune receptor mediates assembly of the inflammasome complex in the presence of microbial ligands, triggering caspase-1 activation and secretion of IL-1β and IL-18. Recent studies suggest that defective Nlrp3 inflammasome signaling in the gut contributes to IBD through increased permeability across the epithelial barrier and the induction of detrimental immune responses against invading commensals. Here, we review and discuss recent advances of the role of the Nlrp3 inflammasome in colitis and colon tumorigenesis.

Section snippets

Nlrp3 in inflammatory bowel disease: for or against?

Crohn's disease (CD) and ulcerative colitis (UC) represent major remitting and relapsing inflammatory disorders of the gastrointestinal tract and are characterized by chronic inflammation, abdominal pain, rectal bleeding, diarrhea and malnutrition [1]. In addition, these inflammatory bowel diseases (IBDs) constitute major risk factors for the development of colorectal cancer [2], thus being responsible for significant health-related costs in the Western world. These ailments differ from each

NLR signaling in IBD

Nlrp3 and the related NLR proteins Nod1 and Nod2 are emerging as crucial regulators of inflammatory responses against commensal microflora in the gut. Notably, the genes encoding Nod1 and Nod2 are mutated in 15–20% of patients suffering from IBD 20, 21, 22. Similar to extracellular TLRs and IL receptors, Nod1 and Nod2 activate the transcription factors NF-κB and AP-1 in Paneth cells, epithelial cells and professional antigen-presenting cells [4]. The peptidoglycan fragments iE-DAP and

Composition and activation of the Nlrp3 inflammasome

Nlrp3 (also known as Nalp3, Cryopyrin, CIAS1, PYPAF1 and CLR1.1) is a 1016 amino acid protein transcribed from NLRP3, which is located on chromosome 1q44. Mutations in NLRP3 underlie a variety of autosomal-dominant periodic fever syndromes known as familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and chronic infantile neurological cutaneous and articular syndrome (CINCA) 26, 27. The protein has a domain architecture characteristic of all NLR members, comprising a

Inflammasome effector genes are risk alleles for IBD

Decreased secretion of the inflammasome cytokine IL-1β was noted in MDP-stimulated myeloid cells of CD patients 44, 45, 46. In addition, polymorphisms in the genes encoding the inflammasome effector IL-18 and the IL-18 receptor accessory protein correlate with increased susceptibility to CD 47, 48. These interesting observations raised the possibility that inflammasomes play a crucial role in IBD. Indeed, a recent study found that SNPs in regulatory elements of Nlrp3 are strongly associated

The Nlrp3 inflammasome in homeostasis of the intestinal epithelium

The crucial role of the Nlrp3 inflammasome in regulating gut homeostasis was strengthened by recent studies examining the molecular mechanisms by which Nlrp3, ASC and caspase-1 control integrity of the intestinal epithelium and modulate immune responses to microbiota in the gut during experimental colitis. While a complete surrogate model displaying all clinical features of human IBD is not available, various mouse models of experimental colitis that are useful for examining important aspects

Nlrp3 activation in cells of the intestinal tract

Because Nlrp3 is expressed in both immune and epithelial cells [60], bone marrow chimera mice were used to determine the cellular compartments contributing to Nlrp3 inflammasome-mediated protection against colitis. Nlrp3 signaling in non-hematopoietic cells was concluded to be crucial because expression of Nlrp3 [18] and caspase-1 [16] in these cells prevented the aggravated disease symptoms seen in DSS-administered Nlrp3/ and casp1/ mice. This effect is likely to originate from intestinal

The inflammasome cytokines IL-1β and IL-18 protect against colitis

Earlier work demonstrating a crucial role for the inflammasome effectors IL-1β and IL-18 in the repair and restitution of the ulcerated epithelium is in agreement with the epithelial guard hypothesis for the Nlrp3 inflammasome discussed above [62]. Once secreted, inflammasome-matured IL-1β and IL-18 might exert their functions through ligation of their respective receptors expressed on intestinal epithelial cells and local immune cells in the gut. Such a role for IL-18 is supported by data

The Nlrp3 inflammasome in colitis-associated tumorigenesis

Inflammation is generally considered a beneficial host response to injury and infection; however, chronic intestinal inflammation, as in IBD patients, is increasingly recognized as a risk factor for the development of colorectal cancer [70]. Recent studies implicate defective NLR activation in priming the intestinal mucosa for increased cell proliferation and tumorigenesis. For instance, defective Nod1 signaling aggravates permeability of the intestinal epithelium during colitis and promotes

Concluding remarks

Our understanding of the biological mechanisms underlying IBD has markedly improved in recent years with the discovery of the major roles of the NLR proteins Nod1 and Nod2 in CD and UC 20, 21, 22, 23. Further progress in understanding the mechanisms underlying IBD was achieved with the discovery that SNPs in the gene encoding Nlrp3 are linked with increased susceptibility to CD [6]. As discussed above, the previously held model of inflammasome signaling being detrimental during colitis 67, 82,

Competing interest

The author declares no competing financial interests.

Acknowledgements

We acknowledge the researchers who have contributed to this field but whose work is not cited or was cited through review articles because of space limitations. This work is supported by National Institute of Health grants AR056296 and AI088177, a NIAMS Centers of Excellence for Influenza Research and Surveillance (CEIRS) grant and the American Lebanese Syrian Associated Charities (ALSAC) to T-D. K. M.L. is supported by the European Union Framework Program 7 Marie-Curie grant 256432 and by the

References (86)

  • P.G. Thomas

    The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1

    Immunity

    (2009)
  • I.C. Allen

    The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA

    Immunity

    (2009)
  • A.G. Hise

    An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans

    Cell Host Microbe

    (2009)
  • L. Feldmeyer

    The inflammasome mediates UVB-induced activation and secretion of interleukin-1beta by keratinocytes

    Curr. Biol.

    (2007)
  • D.A. van Heel

    Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease

    Lancet

    (2005)
  • A.J. van Beelen

    Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells

    Immunity

    (2007)
  • A. Zhernakova

    Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP

    Am. J. Hum. Genet.

    (2008)
  • T.T. Pizarro

    Mouse models for the study of Crohn's disease

    Trends Mol. Med.

    (2003)
  • S. Rakoff-Nahoum

    Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis

    Cell

    (2004)
  • J. Dupaul-Chicoine

    Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases

    Immunity

    (2010)
  • E. Cao

    T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface

    Immunity

    (2007)
  • P. Nava

    Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways

    Immunity

    (2010)
  • T. Kanai

    Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease

    Gastroenterology

    (2001)
  • B. Siegmund

    Interleukin-18 in intestinal inflammation: friend and foe?

    Immunity

    (2010)
  • J.H. Cho

    The genetics and immunopathogenesis of inflammatory bowel disease

    Nat. Rev. Immunol.

    (2008)
  • P. Goyette

    Molecular pathogenesis of inflammatory bowel disease: genotypes, phenotypes and personalized medicine

    Ann. Med.

    (2007)
  • A. Kaser

    Inflammatory bowel disease

    Annu. Rev. Immunol.

    (2010)
  • A.C. Villani

    Common variants in the NLRP3 region contribute to Crohn's disease susceptibility

    Nat. Genet.

    (2009)
  • T.D. Kanneganti

    Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3

    Nature

    (2006)
  • S. Mariathasan

    Cryopyrin activates the inflammasome in response to toxins and ATP

    Nature

    (2006)
  • C.A. Dinarello

    Immunological and inflammatory functions of the interleukin-1 family

    Annu. Rev. Immunol.

    (2009)
  • P.V. Sivakumar

    Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage

    Gut

    (2002)
  • B. Siegmund

    Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production

    Am. J. Physiol. Regul. Integr. Comp. Physiol.

    (2001)
  • C. Bauer

    The ICE inhibitor pralnacasan prevents DSS-induced colitis in C57BL/6 mice and suppresses IP-10 mRNA but not TNF-alpha mRNA expression

    Dig. Dis. Sci.

    (2007)
  • I.C. Allen

    The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer

    J. Exp. Med.

    (2010)
  • S.A. Hirota

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

    Inflamm. Bowel Dis.

    (2010)
  • M.H. Zaki

    IL-18 Production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation

    J. Immunol.

    (2010)
  • J.P. Hugot

    Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease

    Nature

    (2001)
  • J.D. Rioux et al.

    Paths to understanding the genetic basis of autoimmune disease

    Nature

    (2005)
  • D.P. McGovern

    Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease

    Hum. Mol. Genet.

    (2005)
  • L.H. Travassos

    Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry

    Nat. Immunol.

    (2010)
  • J.D. Rioux

    Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis

    Nat. Genet.

    (2007)
  • J. Hampe

    A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1

    Nat. Genet.

    (2007)
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