Neutrophil Caspase-11 Is Essential to Defend against a Cytosol-Invasive Bacterium

Either caspase-1 or caspase-11 can cleave gasdermin D to cause pyroptosis, eliminating intracellular replication niches. We previously showed that macrophages detect Burkholderia thailandensis via NLRC4, triggering the release of interleukin (IL)-18 and driving an essential interferon (IFN)-γ response that primes caspase-11. We now identify the IFN-γ-producing cells as a mixture of natural killer (NK) and T cells. Although both caspase-1 and caspase-11 can cleave gasdermin D in macrophages and neutrophils, we find that NLRC4-activated caspase-1 triggers pyroptosis in macrophages, but this pathway does not trigger pyroptosis in neutrophils. In contrast, caspase-11 triggers pyroptosis in both macrophages and neutrophils. This translates to an absolute requirement for caspase-11 in neutrophils during B. thailandensis infection in mice. We present an example of inflammasome sensors causing diverging outcomes in different cell types. Thus, cell fates are dictated not simply by the pathogen or inflammasome, but also by how the cell is wired to respond to detection events. [Display omitted] •NK and T cells produce IFN-γ to prime caspase-11 during B. thailandensis infection•Caspase-1 and caspase-11 cleave gasdermin D in macrophages and neutrophils•Caspase-11 but not caspase-1 activation leads to pyroptosis in neutrophils•Neutrophil caspase-11 activation is necessary to clear B. thailandensis in vivo Kovacs et al. demonstrate that natural killer and T cells produce IFN-γ to prime caspase-11 during Burkholderia thailandensis infection. They demonstrate that in neutrophils, caspase-1 and caspase-11 activation lead to gasdermin D cleavage, but only caspase-11 activation leads to pyroptosis that is necessary for clearance of this cytosol-invasive pathogen in vivo.