Thromboxane receptor activation in dendritic cells mitigates sepsis by suppressing S100a8/a9-mediated neutrophil recruitment

Dendritic cells (DCs) regulate both innate and adaptive immunity during sepsis. Prostaglandins (PGs), small lipid molecules derived from arachidonic acid via COX enzymes, are crucial regulators of immune homeostasis and inflammation. However, their role in sepsis pathogenesis remains poorly defined. In this study, we identified a significant negative correlation between DC depletion and disease severity in patients with sepsis. Thromboxane (TX) A2 receptor (TP) expression was markedly reduced in blood DCs of patients with sepsis. Patients with low DC-TP expression exhibited an increased blood neutrophil count and a worsening of disease severity. In murine models of sepsis induced by cecal ligation and puncture and lipopolysaccharide challenge, DC-specific TP deficiency exacerbated sepsis by promoting S100a8/a9-mediated neutrophil recruitment, and subsequently neutrophil extracellular trap (NET) formation and lung injury. Genetic and pharmacological inhibition of S100a8/a9-TLR4 axis protected TP-deficient mice from fatal sepsis. Mechanistically, TP signaling suppressed S100a8/a9 expression in DCs via PKCδ-Stat1 signaling, thereby restricting neutrophil infiltration and NETs formation. Finally, the targeted activation of TP in DCs using the nanodrug, DCpep-U-46619, effectively alleviated sepsis-induced lung injury in mice. These findings established TP as a critical immunoregulatory receptor in DCs, highlighting its potential as a therapeutic target for sepsis.