Trends in Immunology
ReviewThe Nlrp3 inflammasome: contributions to intestinal homeostasis
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
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