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

Nature Immunology volume 11, pages 1136–1142 (2010)Cite this article

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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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Figure 1: Characterization of flagellin-expressing S. typhimurium.
Figure 2: Flagellin expression attenuates S. typhimurium in vivo.
Figure 3: Different roles for ASC in NLRC4 signaling.
Figure 4: Evidence of pyroptosis in vivo.
Figure 5: ST-FliCON bacteria are released from macrophages and cleared by ROS.
Figure 6: ST-FliCON bacteria accumulate in neutrophils.
Figure 7: Sustained NLRC4 activation causes tissue damage.

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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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Authors and Affiliations

  1. Institute for Systems Biology, Seattle, Washington, USA

    Edward A Miao, Irina A Leaf, Dat P Mao, Monica Dors, Sarah E Warren & Alan Aderem

  2. Department of Comparative Medicine, University of Washington, Seattle, Washington, USA

    Piper M Treuting

  3. Pulmonary, Critical Care, Allergy and Sleep Medicine, The Dorothy M. Davis Heart and Lung Research Institute, Ohio State University, Columbus, Ohio, USA

    Anasuya Sarkar & Mark D Wewers

  4. Department of Immunology, University of Washington, Seattle, Washington, USA

    Sarah E Warren

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Contributions

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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Correspondence to Edward A Miao or Alan Aderem.

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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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