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Superoxide dismutase 1 regulates caspase-1 and endotoxic shock

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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Figure 1: SOD1 deficiency blocks the activation of caspase-1 and maturation of IL-1β and IL-18.
Figure 2: Mitogen-activated protein kinase and NF-κB signaling and the production of caspase-1-independent cytokines are not affected by SOD1 deficiency.
Figure 3: Greater production of superoxide inhibits caspase-1.
Figure 4: SOD1 deficiency results in a lower cellular redox potential and inhibits caspase-1 by glutathionylation.
Figure 5: Redox-sensitive cysteine residues regulate caspase-1 activation.
Figure 6: Caspase-1 inhibition in physiological conditions is oxygen dependent.
Figure 7: SOD1-deficient mice have lower amounts of caspase-1-dependent cytokines and are more resistant to LPS-induced shock.

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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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Correspondence to Arturo Zychlinsky.

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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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