Su, Chen et al. show that sepsis-derived S100A8/A9 induces GSDMD-dependent platelet pyroptosis via the TLR4/ROS/NLRP3/caspase 1 pathway, leading to the release of ox-mtDNA contributing to neutrophil extracellular traps (NET) formation. NET in turn release S100A8/A9 and accelerate platelet pyroptosis, forming a positive feedback loop, thereby amplifying the production of proinflammatory cytokines. GSDMD deficiency in platelets or pharmacological inhibition of S100A9 using Paquinimod can break this detrimental feedback loop, thus ameliorating excessive NET-mediated inflammation in mouse models of severe sepsis.
- Meiling Su
- Chaofei Chen
- Wai Ho Tang
