Canonical Inflammasomes Drive IFN-γ to Prime Caspase-11 in Defense against a Cytosol-Invasive Bacterium

• Published in: Cell host & microbe 2015-09, Vol.18 (3), p.320-332
• Main Authors: Aachoui, Youssef, Kajiwara, Yuji, Leaf, Irina A., Mao, Dat, Ting, Jenny P.-Y., Coers, Jörn, Aderem, Alan, Buxbaum, Joseph D., Miao, Edward A.
• Format: Article
• Language: English
• Subjects: Animals; Burkholderia - immunology; Caspase 1 - metabolism; Caspases - metabolism; Caspases, Initiator - metabolism; Cytosol - microbiology; Humans; Inflammasomes - metabolism; Interferon-gamma - metabolism; Interleukin-18 - metabolism; Mice; Mice, Transgenic; Signal Transduction
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2015.07.016

The inflammatory caspases 1 and 11 are activated in response to different agonists and act independently to induce pyroptosis. In the context of IL-1β/IL-18 secretion, however, in vitro studies indicate that caspase-11 acts upstream of NLRP3 and caspase-1. By contrast, studying infection in vivo by the cytosol-invasive bacterium Burkholderia thailandensis, we find that caspase-1 activity is required upstream of caspase-11 to control infection. Caspase-1-activated IL-18 induces IFN-γ to prime caspase-11 and rapidly clear B. thailandensis infection. In the absence of IL-18, bacterial burdens persist, eventually triggering other signals that induce IFN-γ. Whereas IFN-γ was essential, endogenous type I interferons were insufficient to prime caspase-11. Although mice transgenic for caspase-4, the human ortholog of caspase-11, cleared B. thailandensis in vivo, they did not strictly require IFN-γ priming. Thus, caspase-1 provides priming signals upstream of caspase-11 but not caspase-4 during murine defense against a cytosol-invasive bacterium. [Display omitted] •Caspase-1 and -11 differentially protect against cytosol-invasive B. thailandensis•Canonical inflammasome NLRC4- or NLRP3-activated IL-18 is required for defense•IL-18 drives a rapid IFN-γ response, which is critical for caspase-11 priming in vivo•A CASP4 transgene complements Casp1−/−Casp11−/− mice independently of IFN-γ Caspase-1 and -11 are critical in defense against the cytosol-invasive bacterium Burkholderia thailandensis. Aachoui et al. show that caspase-1-driven IL-18 induces IFN-γ to prime caspase-11 for rapid defense against B. thailandensis in vivo. Unlike murine caspase-11, its human ortholog caspase-4 may not strictly require IFN-γ priming to defend against B. thailandensis.