Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria

Macrophages mediate crucial innate immune responses via caspase-1-dependent processing and secretion of IL-1β and IL-18. While wild type Salmonella typhimurium infection is lethal to mice, a strain that persistently expresses flagellin was cleared by the cytosolic flagellin detection pathway via NLRC4 activation of caspase-1; however, this clearance was independent of IL-1β and IL-18. Instead, caspase-1 induced pyroptotic cell death, released bacteria from macrophages and exposed them to uptake and killing by reactive oxygen species in neutrophils. Similarly, caspase-1 cleared unmanipulated Legionella and Burkholderia by cytokine-independent mechanisms. This demonstrates for the first time that caspase-1 clears intracellular bacteria in vivo independent of IL-1β and IL-18, and establishes pyroptosis as an efficient mechanism of bacterial clearance by the innate immune system.