title: Inflammasome activation by Campylobacter jejuni.
abstract: The Gram-negative pathogen Campylobacter jejuni is the most common cause of bacterial foodborne disease worldwide. The mechanisms that lead to bacterial invasion of eukaryotic cells and massive intestinal inflammation are still unknown. In this study, we report that C. jejuni infection of mouse macrophages induces upregulation of pro-IL-1β transcript and secretion of IL-1β without eliciting cell death. Immunoblotting indicated cleavage of caspase-1 and IL-1β in infected cells. In bone marrow-derived macrophages from different knockout mice, IL-1β secretion was found to require NLRP3, ASC, and caspase-1/11 but not NLRC4. In contrast to NLRP3 activation by ATP, C. jejuni activation did not require priming of these macrophages. C. jejuni also activated the NLRP3 inflammasome in human macrophages as indicated by the presence of ASC foci and caspase-1-positive cells. Analysis of a vast array of C. jejuni mutants with defects in capsule formation, LPS biosynthesis, chemotaxis, flagella synthesis and flagellin (-like) secretion, type 6 secretion system needle protein, or cytolethal distending toxin revealed a direct correlation between the number of intracellular bacteria and NLRP3 inflammasome activation. The C. jejuni invasion-related activation of the NLRP3 inflammasome without cytotoxicity and even in nonprimed cells extends the known repertoire of bacterial inflammasome activation and likely contributes to C. jejuni-induced intestinal inflammation.
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University, 3584 CL Utrecht, the Netherlands;
authors.forename: Lieneke I
authors.initials: LI
authors.lastname: Bouwman
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; and Howard Hughes Medical Institute, Yale University, New Haven, CT 06520.
authors.forename: Marcel R
authors.initials: MR
authors.lastname: de Zoete
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University, 3584 CL Utrecht, the Netherlands;
authors.forename: Nancy M C
authors.initials: NM
authors.lastname: Bleumink-Pluym
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; and Howard Hughes Medical Institute, Yale University, New Haven, CT 06520.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University, 3584 CL Utrecht, the Netherlands; j.vanputten@uu.nl.
authors.forename: Jos P M
authors.initials: JP
authors.lastname: van Putten
mesh_terms: D000818:Animals; D002169:Campylobacter Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016123:Campylobacter jejuni / Q000235:genetics / Q000276:immunology*; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D020170:Caspase 1