Cardiolipin Inhibits the Noncanonical Inflammasome by Preventing LPS Binding to Caspase 4/11 to Mitigate Endotoxemia in Vivo

In Gram-negative bacterial sepsis, excessive caspase 4/11 activation in response to circulating bacterial lipid LPS (endotoxemia) can cause organ damage and mortality. Current inhibitors of caspase 4/11 also block caspase 1 activity and are therefore not appealing clinical candidates for treating Gram-negative sepsis. Here, we identify double-unsaturated 18:2 cardiolipin as a selective inhibitor of caspase 4/11-dependent inflammatory cytokine secretion and pyroptosis, without affecting caspase-1 responses. Cardiolipin targets the CARD domain of caspase 4/11, impeding its interaction with LPS to restrain caspase 4/11 activation, thereby suppressing endotoxemia-induced systemic inflammation in vivo. Thus, we present cardiolipin as a promising candidate for preventing endotoxemia- induced sequelae in sepsis while preserving caspase-1-driven anti-microbial immune responses. By identifying cardiolipin as a specific caspase 4/11 inhibitor, we provide an urgently-needed tool for studying caspase 4/11 functions in inflammatory pathways, and open the way to studies of noncanonical inflammasome regulation by endogenous cardiolipin.