37: Caspase-11 controls inflammasome activation in response to bacterial secretion systems that access the host cell cytosol

Abstract

Inflammasome activation is important for antimicrobial defense because it induces cell death and regulates the secretion of IL-1 family cytokines. The inflammasome activates caspase-1 to process and secrete IL-1 β . However, the mechanisms governing IL-1 α release are less clear. Recently, a non-canonical inflammasome was described that activates caspase-11 and mediates pyroptosis and release of IL-1 α and IL-1 β through TRIF-dependent interferon production. However, it is unknown whether additional bacterial signals trigger caspase-11 activation. Many bacterial pathogens use specialized secretion systems to translocate effector proteins into the host cell cytosol. These secretion systems can also deliver flagellin into the cytosol, which triggers caspase-1 activation and pyroptosis. However, specialized secretion systems still induce inflammasome activation in the absence of flagellin, but the pathways that mediate this response are unclear. We observe rapid inflammasome activation in response to the type IV or type III secretion systems of Legionella pneumophila and Yersinia pseudotuberculosis . Unlike IL-1 β secretion, IL-1 α secretion does not require caspase-1. Instead, caspase-11 is required for both IL-1 α secretion and cell death in response to the activity of these secretion systems. Caspase-11 promotes IL-1 β release through the NLRP3/ASC inflammasome, but caspase-11-dependent release of IL-1 α is independent of NLRP3/ASC, NAIP5/NLRC4, TRIF, and type I interferon signaling. Furthermore, we find both overlapping and non-redundant roles for IL-1 α and IL-1 β 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 that is critical for host defense in vivo.