title: NLRC4 expression in intestinal epithelial cells mediates protection against an enteric pathogen.
abstract: The inflammasomes have an important role in connecting the detection of endogenous and microbial danger signals to caspase-1 activation and induction of protective immune responses. NLRC4 is a cytosolic NOD (nucleotide binding and oligomerization domain)-like receptor (NLR) that can trigger inflammasome formation in response to bacterial flagellin, an immunodominant antigen in the intestine. To characterize the role of NLRC4 in bacterially triggered intestinal inflammation, we used the murine pathogen Citrobacter rodentium, an extracellular, attaching/effacing bacterium similar to enterohemorrhagic Escherichia coli and enteropathogenic E. coli. Following infection with C. rodentium, we found that Nlrc4(-/-) mice developed more severe weight loss, increased bacterial colonization levels, and exacerbated intestinal inflammation compared with wild-type counterparts. Nlrc4(-/-) mice mounted robust adaptive immune responses but were unable to control early colonization by C. rodentium, suggesting that a defect in innate immunity was responsible. Experiments using bone marrow (BM) chimeras revealed that the protective effects of NLRC4 were dependent on its expression in non-hematopoietic cells, and quantitative PCR (Q-PCR) analyses revealed that NLRC4 was highly expressed in epithelial crypts but not in intestinal stroma. Thus, early NLRC4 sensing in intestinal epithelial cells regulates colonization by an extracellular bacterial pathogen and limits subsequent intestinal damage.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Nordlander
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: J
authors.initials: J
authors.lastname: Pott
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Maloy
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D044082:Citrobacter rodentium; D004195:Disease Models, Animal; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D004847:Epithelial Cells / Q000378:metabolism*; D004926:Escherichia coli; D015870:Gene Expression; D054884:Host-Pathogen Interactions / Q000235:genetics* / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D020382:Interleukin-18 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D020382:Interleukin-18; C512299:Ipaf protein, mouse