Abstract
Caspase-1 serves an essential function in the initiation of inflammation by proteolytically maturing the cytokines interleukin 1β and interleukin 18. Several Nod-like receptors activate caspase-1 in response to microbial and 'danger' signals by assembling cytosolic protein complexes called 'inflammasomes'. We show here that superoxide dismutase 1 (SOD1) regulates caspase-1 activation. In SOD1-deficient macrophages, higher superoxide production decreased the cellular redox potential and specifically inhibited caspase-1 by reversible oxidation and glutathionylation of the redox-sensitive cysteine residues Cys397 and Cys362. Conversely, hypoxic conditions abrogated caspase-1 inhibition. In vivo, SOD1-deficient mice produced less caspase-1-dependent cytokines and were less susceptible to lipopolysaccharide-induced septic shock. Our findings identify a physiological post-translational mechanism in the control of caspase-1-mediated inflammatory processes.
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Acknowledgements
We thank members of the Zychlinsky laboratory for discussions; B. Raupach and J. de Diego for advice; and M. Schmidt and J. Lambers for technical assistance.
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Meissner, F., Molawi, K. & Zychlinsky, A. Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nat Immunol 9, 866–872 (2008). https://doi.org/10.1038/ni.1633
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DOI: https://doi.org/10.1038/ni.1633
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