title: Nlrp3 activation in the intestinal epithelium protects against a mucosal pathogen.
abstract: Polymorphisms in the intracellular pattern recognition receptor gene NLRP3 (NLR family, pyrin domain containing 3) have been associated with susceptibility to Crohn's disease, a type of inflammatory bowel disease. Following tissue damage or infection, NLRP3 triggers the formation of inflammasomes, containing NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD domain), and caspase-1, that mediate secretion of interleukin (IL)-1β and IL-18. However, the precise role of NLRP3 inflammasomes in mucosal inflammation and barrier protection remains unclear. Here we show that upon infection with the attaching/effacing intestinal pathogen Citrobacter rodentium, Nlrp3(-/-) and Asc(-/-) mice displayed increased bacterial colonization and dispersion, more severe weight loss, and exacerbated intestinal inflammation. Analyses of irradiation bone marrow chimeras revealed that protection from disease was mediated through Nlrp3 activation in nonhematopoietic cells and was initiated very early after infection. Thus, early activation of Nlrp3 in intestinal epithelial cells limits pathogen colonization and prevents subsequent pathology, potentially providing a functional link between NLRP3 polymorphisms and susceptibility to inflammatory bowel disease.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK.
authors.forename: George X
authors.initials: GX
authors.lastname: Song-Zhao
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK.
authors.forename: Naren
authors.initials: N
authors.lastname: Srinivasan
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK.
authors.forename: Johanna
authors.initials: J
authors.lastname: Pott
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: Dilair
authors.initials: D
authors.lastname: Baban
authors.affiliation: MRC Centre for Molecular Bacteriology and Infection, Division of Cell and Molecular Biology, Imperial College London, London, UK.
authors.forename: Gad
authors.initials: G
authors.lastname: Frankel
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Maloy
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D044082:Citrobacter rodentium; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000235:genetics* / Q000276:immunology; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D054884:Host-Pathogen Interactions / Q000235:genetics* / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D020170:Caspase 1