title: Caspase-11 activation in response to bacterial secretion systems that access the host cytosol.
abstract: Inflammasome activation is important for antimicrobial defense because it induces cell death and regulates the secretion of IL-1 family cytokines, which play a critical role in inflammatory responses. The inflammasome activates caspase-1 to process and secrete IL-1β. However, the mechanisms governing IL-1α release are less clear. Recently, a non-canonical inflammasome was described that activates caspase-11 and mediates pyroptosis and release of IL-1α and IL-1β. Caspase-11 activation in response to Gram-negative bacteria requires Toll-like receptor 4 (TLR4) and TIR-domain-containing adaptor-inducing interferon-β (TRIF)-dependent interferon production. Whether additional bacterial signals trigger caspase-11 activation is unknown. Many bacterial pathogens use specialized secretion systems to translocate effector proteins into the cytosol of host cells. These secretion systems can also deliver flagellin into the cytosol, which triggers caspase-1 activation and pyroptosis. However, even in the absence of flagellin, these secretion systems induce inflammasome activation and the release of IL-1α and IL-1β, but the inflammasome pathways that mediate this response are unclear. We observe rapid IL-1α and IL-1β release and cell death in response to the type IV or type III secretion systems of Legionella pneumophila and Yersinia pseudotuberculosis. Unlike IL-1β, IL-1α secretion does not require caspase-1. Instead, caspase-11 activation is required for both IL-1α secretion and cell death in response to the activity of these secretion systems. Interestingly, whereas caspase-11 promotes IL-1β release in response to the type IV secretion system through the NLRP3/ASC inflammasome, caspase-11-dependent release of IL-1α is independent of both the NAIP5/NLRC4 and NLRP3/ASC inflammasomes as well as TRIF and type I interferon signaling. Furthermore, we find both overlapping and non-redundant roles for IL-1α and IL-1β in mediating neutrophil recruitment and bacterial clearance in response to pulmonary infection by L. pneumophila. Our findings demonstrate that virulent, but not avirulent, bacteria trigger a rapid caspase-11-dependent innate immune response important for host defense.
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Cierra N
authors.initials: CN
authors.lastname: Casson
authors.forename: Alan M
authors.initials: AM
authors.lastname: Copenhaver
authors.forename: Erin E
authors.initials: EE
authors.lastname: Zwack
authors.forename: Hieu T
authors.initials: HT
authors.lastname: Nguyen
authors.forename: Till
authors.initials: T
authors.lastname: Strowig
authors.forename: Bahar
authors.initials: B
authors.lastname: Javdan
authors.forename: William P
authors.initials: WP
authors.lastname: Bradley
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Fung
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Igor E
authors.initials: IE
authors.lastname: Brodsky
authors.forename: Sunny
authors.initials: S
authors.lastname: Shin
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology; D058947:Bacterial Secretion Systems / Q000276:immunology*; D002135:Calcium-Binding Proteins / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology; D020169:Caspases / Q000235:genetics / Q000276:immunology*; D053471:Caspases, Initiator; D002460:Cell Line; D003600:Cytosol / Q000276:immunology* / Q000382:microbiology; D004789:Enzyme Activation / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D053582:Interleukin-1alpha / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D016952:Legionella pneumophila / Q000276:immunology* / Q000472:pathogenicity; D007877:Legionnaires' Disease / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D058947:Bacterial Secretion Systems; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator