Myeloid cell identity shapes cell death decisions during inflammasome signalling

KW Chen1, CJ Gross2, F Vasquez Sotomayor1, KJ Stacey3, J Tschopp4, MJ Sweet1 and K Schroder1

  1. Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia
  2. Institut fur Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universitat Munchen, 81675 Munich, Germany
  3. School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia 4072, Australia
  4. Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland

Macrophage and dendritic cell inflammasomes drive potent innate immune responses against intracellular pathogens, by eliciting rapid caspase-1-dependent pro-inflammatory cytokine production (e.g. interleukins (IL)-1β and -18) and pyroptotic cell death. The contribution of other cell types to inflammasome-mediated host defense had not been examined in detail. Here we demonstrate that neutrophils, typically viewed as cellular targets of inflammasome-dependent IL-1β, themselves signal via a variety of inflammasomes, and are a major cell compartment for IL-1β production during in vivo infection with Salmonella. Importantly, unlike macrophages, neutrophils do not undergo pyroptosis upon in vitro or in vivo NLRC4, NLRP3 or AIM2 inflammasome activation. The ability of neutrophils to resist caspase-1-mediated death is unique amongst inflammasome-signaling cells so far described. Their continued viability allows neutrophils to sustain IL-1β production at a site of infection, and exert their crucial inflammasome-independent antimicrobial effector functions to clear infection. This work reveals neutrophils as a surprising new cellular player in inflammasome-mediated host defence during in vivo bacterial infection, and highlights how myeloid cell identity can have a major impact on innate immune signalling pathways.