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) A(2) receptor (TP) expression was markedly reduced in the blood DCs of patients with sepsis. Patients with low DC-TP expression presented increased blood neutrophil counts and worsened 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 the 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 NET formation. Finally, the targeted activation of TP in DCs via the nanodrug DCpep-U-46619 effectively alleviated sepsis-induced lung injury in mice. These findings establish TP as a critical immunoregulatory receptor in DCs, highlighting its potential as a therapeutic target for sepsis.