Superoxide dismutase 1 regulates caspase-1 and endotoxic shock

Nat Immunol. 2008 Aug;9(8):866-72. doi: 10.1038/ni.1633. Epub 2008 Jul 6.

Abstract

Caspase-1 serves an essential function in the initiation of inflammation by proteolytically maturing the cytokines interleukin 1 beta 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.

MeSH terms

  • Animals
  • Caspase 1 / metabolism*
  • Endotoxins / metabolism*
  • Enzyme Activation
  • Inflammation / immunology*
  • Lipopolysaccharides / metabolism
  • Macrophages / metabolism
  • Mice
  • Shock, Septic*
  • Superoxide Dismutase / deficiency
  • Superoxide Dismutase / immunology
  • Superoxide Dismutase / metabolism*
  • Superoxide Dismutase-1

Substances

  • Endotoxins
  • Lipopolysaccharides
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Caspase 1