title: Salmonella infection induces recruitment of Caspase-8 to the inflammasome to modulate IL-1β production.
abstract: Nucleotide-binding oligomerization domain-like receptors (NLRs) detect pathogens and danger-associated signals within the cell. Salmonella enterica serovar Typhimurium, an intracellular pathogen, activates caspase-1 required for the processing of the proinflammatory cytokines, pro-IL-1β and pro-IL-18, and pyroptosis. In this study, we show that Salmonella infection induces the formation of an apoptosis-associated specklike protein containing a CARD (ASC)-Caspase-8-Caspase-1 inflammasome in macrophages. Caspase-8 and caspase-1 are recruited to the ASC focus independently of one other. Salmonella infection initiates caspase-8 proteolysis in a manner dependent on NLRC4 and ASC, but not NLRP3, caspase-1 or caspase-11. Caspase-8 primarily mediates the synthesis of pro-IL-1β, but is dispensable for Salmonella-induced cell death. Overall, our findings highlight that the ASC inflammasome can recruit different members of the caspase family to induce distinct effector functions in response to Salmonella infection.
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, United Kingdom;
authors.forename: Si Ming
authors.initials: SM
authors.lastname: Man
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Tourlomousis
authors.forename: Lee
authors.initials: L
authors.lastname: Hopkins
authors.forename: Tom P
authors.initials: TP
authors.lastname: Monie
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Clare E
authors.initials: CE
authors.lastname: Bryant
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001854:Bone Marrow Cells; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D020169:Caspases; D053471:Caspases, Initiator; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D058847:Inflammasomes / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics; D012480:Salmonella Infections / Q000276:immunology* / Q000378:metabolism; D012486:Salmonella typhimurium / Q000276:immunology; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; C101136:Casp4 protein, mouse; D053181:Caspase 8; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1