Cardiolipin Inhibits the Noncanonical Inflammasome by Preventing LPS Binding to Caspase 4/11 to Mitigate Endotoxemia in Vivo
Pizzuto, M.; Monteleone, M.; Burgener, S. S.; Began, J.; Kurera, M.; Chia, J. R.; Frampton, E.; Crawford, J.; Oliveira, M.; Kenney, K. M.; Coombs, J. R.; Yamamoto, M.; Man, S. M.; Broz, P.; Pelegrin, P.; Schroder, K.
Show abstract
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.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- LRRC8A regulates hypotonicity-induced NLRP3 inflammasome activation 97%
- ER-to-lysosome Ca2+ refilling followed by K+ efflux-coupled store-operated Ca2+ entry in inflammasome activation and metabolic inflammation 96%
- A highly conserved lipase deacylates oxidized phospholipids and ameliorates acute lung injury 96%
Similar papers in this journal
- The ASC Speck And NLRP3 Inflammasome Function Are Spatially And Temporally Distinct 96%
- Persistent oxidative stress and inflammasome activation in CD14 high CD16 - monocytes from COVID-19 patients 95%
- Determining distinct roles of IL-1α through generation of an IL-1α knockout mouse with no defect in IL-1β expression 95%
Similar papers in this journal
Similar papers in this journal
- Aberrant localization of CDC42 C-terminal variants to the Golgi apparatus drives pyrin inflammasome-dependent autoinflammation 94%
- P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection 94%
- Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signalling 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.