Malvina Pizzuto,Mercedes Monteleone,Sabrina Sofia Burgener,Jakub Began,Melan Kurera,Jing Rong Chia,Emmanuelle Frampton,Joanna Crawford,Monalisa Oliveira,Kirsten M Kenney,Jared R Coombs,Masahiro Yamamoto,Si Ming Man,Petr Broz,Pablo Pelegrin,Kate Schroder
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Cardiolipin inhibits the non-canonical inflammasome by preventing LPS binding to caspase-4/11.
Caspase-4 and caspase-11 (CASP4/11) sense bacterial lipopolysaccharide (LPS). Currently available inhibitors of CASP4/11 also block the activity of caspase-1 (CASP1), which restricts their usefulness in the study of CASP4/11 functions, as well as their clinical potential for the treatment of LPS-linked diseases through CASP4/11 inhibition. Here, we identify mitochondrial cardiolipin as a selective inhibitor of CASP4/11-dependent cell death and inflammatory cytokine secretion, without affecting CASP1 function. Cardiolipin targets the CARD domain of CASP4/11, impeding its interaction with LPS to restrain CASP4/11 activation, thereby suppressing LPS-induced systemic inflammation in vivo. By identifying cardiolipin as a selective inhibitor of CASP4/11, we provide an urgently needed tool for studying caspase-4/11 and noncanonical inflammasome functions in inflammatory pathways and LPS-induced pathogenesis.
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