Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Macrophages mediate innate immune responses by caspase-1-dependent processing and secretion of IL-1β and IL-18. However, a strain of Salmonella typhimurium that persistently expresses flagellin was cleared by the cytosolic flagellin detection pathway via NLRC4 activation of caspase-1, independent of IL-1β and IL-18. Instead, caspase-1 induced pyroptotic cell death, releasing bacteria from macrophages and exposing 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 that caspase-1 can clear intracellular bacteria in vivo without relying on IL-1β and IL-18, establishing pyroptosis as an efficient mechanism of bacterial clearance by the innate immune system. The study also shows that pyroptosis is a programmed, caspase-1-dependent, and pro-inflammatory form of cell death. In contrast, apoptosis is a non-inflammatory, caspase 3 and 7-dependent process. The findings indicate that caspase-1-mediated pyroptosis is a key innate immune mechanism for clearing intracellular pathogens, independent of IL-1β and IL-18. The study further reveals that pyroptosis can lead to the release of bacteria from macrophages, which are then phagocytosed and killed by neutrophils. The results suggest that pyroptosis is a beneficial host defense mechanism in wild-type mice but can cause tissue damage in the absence of downstream neutrophil killing. The study also highlights the role of the NLRC4 inflammasome in detecting cytosolic flagellin and activating caspase-1, leading to pyroptosis and bacterial clearance. The findings provide new insights into the role of caspase-1 in innate immune responses and the mechanisms by which pathogens evade immune detection.Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Macrophages mediate innate immune responses by caspase-1-dependent processing and secretion of IL-1β and IL-18. However, a strain of Salmonella typhimurium that persistently expresses flagellin was cleared by the cytosolic flagellin detection pathway via NLRC4 activation of caspase-1, independent of IL-1β and IL-18. Instead, caspase-1 induced pyroptotic cell death, releasing bacteria from macrophages and exposing 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 that caspase-1 can clear intracellular bacteria in vivo without relying on IL-1β and IL-18, establishing pyroptosis as an efficient mechanism of bacterial clearance by the innate immune system. The study also shows that pyroptosis is a programmed, caspase-1-dependent, and pro-inflammatory form of cell death. In contrast, apoptosis is a non-inflammatory, caspase 3 and 7-dependent process. The findings indicate that caspase-1-mediated pyroptosis is a key innate immune mechanism for clearing intracellular pathogens, independent of IL-1β and IL-18. The study further reveals that pyroptosis can lead to the release of bacteria from macrophages, which are then phagocytosed and killed by neutrophils. The results suggest that pyroptosis is a beneficial host defense mechanism in wild-type mice but can cause tissue damage in the absence of downstream neutrophil killing. The study also highlights the role of the NLRC4 inflammasome in detecting cytosolic flagellin and activating caspase-1, leading to pyroptosis and bacterial clearance. The findings provide new insights into the role of caspase-1 in innate immune responses and the mechanisms by which pathogens evade immune detection.