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Caspase-1 activity is required to bypass macrophage apoptosis upon Salmonella infection

Abstract

Here we report AWP28, an activity-based probe that can be used to biochemically monitor caspase-1 activation in response to proinflammatory stimuli. Using AWP28, we show that apoptosis is triggered upon Salmonella enterica var. Typhimurium infection in primary mouse bone marrow macrophages lacking caspase-1. Furthermore, we report that upon Salmonella infection, inflammasome-mediated caspase-1 activity is required to bypass apoptosis in favor of proinflammatory pyroptotic cell death.

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Figure 1: AWP28 is an optimized caspase activity-based probe.
Figure 2: S. Typhimurium infection triggers apoptosis in the absence of inflammasome-mediated caspase-1 activation.
Figure 3: Caspase-1 activity is required to bypass apoptosis upon infection.

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Acknowledgements

We thank the Bogyo and Monack labs for useful discussions and help with macrophage harvesting. We thank S. Lynch for help with NMR. We thank B. Van Raam for apoptosis marker protocols and S. Snipas and E. Deu for helpful discussions about kinetics. Caspases 3, 4, 6, 7 and 8 and substrates were provided by the Salvesen lab (Sanford Burnham Medical Research Institute); granzyme B and substrate was provided by the Craik lab (University of California–San Francisco), caspase-1–specific antibody was provided by P. Vandenabeele (VIB, Ghent University). This work was supported by US National Institutes of Health (NIH) grants R01EB005011 and R01AI088541 to M.B. A.W.P. was supported by an US National Science Foundation Graduate Research Fellowship. P.B. is supported by a Stanford Institute for Immunity, Transplantation and Infection Young Investigator Award and was supported by the Swiss National Science Foundation and the Human Frontiers in Science Program. A.S. is supported by the NIH grant K99 GM092934. M.B. and D.M.M. are supported by the Burroughs Wellcome Foundation.

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A.W.P., P.B., A.S., D.M.M. and M.B. designed the experiments. A.W.P. and P.B. performed the experiments. A.W.P., P.B., A.S., D.M.M. and M.B. analyzed the data. A.W.P. and M.B. wrote the manuscript.

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Correspondence to Matthew Bogyo.

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The authors declare no competing financial interests.

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Puri, A., Broz, P., Shen, A. et al. Caspase-1 activity is required to bypass macrophage apoptosis upon Salmonella infection. Nat Chem Biol 8, 745–747 (2012). https://doi.org/10.1038/nchembio.1023

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