10.1371/journal.ppat.1003400 Cierra N. Casson Cierra N. Casson Alan M. Copenhaver Alan M. Copenhaver Erin E. Zwack Erin E. Zwack Hieu T. Nguyen Hieu T. Nguyen Till Strowig Till Strowig Bahar Javdan Bahar Javdan William P. Bradley William P. Bradley Thomas C. Fung Thomas C. Fung Richard A. Flavell Richard A. Flavell Igor E. Brodsky Igor E. Brodsky Sunny Shin Sunny Shin Caspase-11 Activation in Response to Bacterial Secretion Systems that Access the Host Cytosol Public Library of Science 2013 immunology Immune cells monocytes immunity Immune activation Immune defense Immunity to infections Innate immunity microbiology Bacterial pathogens Gram negative inflammation Host-pathogen interaction pathogenesis activation bacterial secretion systems 2013-06-06 01:04:19 Dataset https://plos.figshare.com/articles/dataset/_Caspase_11_Activation_in_Response_to_Bacterial_Secretion_Systems_that_Access_the_Host_Cytosol_/713859 <div><p>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 <i>Legionella pneumophila</i> and <i>Yersinia pseudotuberculosis</i>. 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 <i>L. pneumophila</i>. Our findings demonstrate that virulent, but not avirulent, bacteria trigger a rapid caspase-11-dependent innate immune response important for host defense.</p></div>