Abstract
Macrophages mediate crucial innate immune responses via caspase-1-dependent processing and secretion of interleukin 1β (IL-1β) and IL-18. Although infection with wild-type Salmonella typhimurium is lethal to mice, we show here that a strain that persistently expresses flagellin was cleared by the cytosolic flagellin-detection pathway through the activation of caspase-1 by the NLRC4 inflammasome; however, this clearance was independent of IL-1β and IL-18. Instead, caspase-1-induced pyroptotic cell death released bacteria from macrophages and exposed the bacteria to uptake and killing by reactive oxygen species in neutrophils. Similarly, activation of caspase-1 cleared unmanipulated Legionella pneumophila and Burkholderia thailandensis by cytokine-independent mechanisms. This demonstrates that activation of caspase-1 clears intracellular bacteria in vivo independently of IL-1β and IL-18 and establishes pyroptosis as an efficient mechanism of bacterial clearance by the innate immune system.
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Acknowledgements
We thank D. Rodriguez for managing the mouse colony and members of the Aderem laboratory for critical review of the manuscript. Supported by the US National Institutes of Health (U54 AI057141 and AI052286).
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E.A.M., I.A.L. and A.A. conceived of the research plan and wrote the manuscript; E.A.M., I.A.L., D.P.M., M.D., A.S. and M.D.W. planned and did experiments; and P.M.T. planned and did histological analyses.
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Miao, E., Leaf, I., Treuting, P. et al. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol 11, 1136–1142 (2010). https://doi.org/10.1038/ni.1960
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DOI: https://doi.org/10.1038/ni.1960
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