This study reveals the critical role of the thromboxane receptor (TP) in dendritic cells in regulating S100a8/a9-mediated neutrophil recruitment, suggesting that TP could serve as a potential therapeutic target for immune modulation in sepsis.
Literature Overview
The article titled 'Thromboxane receptor activation in dendritic cells mitigates sepsis by suppressing S100a8/a9-mediated neutrophil recruitment,' published in Signal Transduction and Targeted Therapy, reviews and summarizes the immunomodulatory functions of dendritic cells (DCs) in sepsis, particularly the role of the thromboxane A2 receptor (TP). The study finds that TP expression in DCs is significantly downregulated in both septic patients and murine sepsis models, and correlates negatively with disease severity. TP deficiency exacerbates sepsis by promoting S100a8/a9-dependent neutrophil infiltration and neutrophil extracellular trap (NET) formation, ultimately leading to lung injury. Mechanistically, TP suppresses S100a8/a9 expression in DCs via the PKCδ-Stat1 signaling pathway. Furthermore, the research team developed a DC-targeted nanodrug, DCpep-U-46619, which specifically activates TP in DCs and effectively alleviates sepsis symptoms in mice. These findings establish the immunomodulatory function of TP in DCs and highlight its potential as a novel therapeutic target for sepsis.Background Knowledge
Sepsis is a life-threatening systemic inflammatory response syndrome triggered by infection, frequently leading to multiple organ dysfunction and representing a major cause of mortality in intensive care units (ICUs). Despite advances in supportive care, the lack of specific immunomodulatory therapies remains a clinical bottleneck. Dendritic cells, as key antigen-presenting cells bridging innate and adaptive immunity, exhibit functional dysregulation during sepsis—such as impaired antigen presentation and imbalanced pro- and anti-inflammatory cytokine production—though the underlying regulatory mechanisms are not fully understood. Prostaglandins (PGs), lipid mediators derived from arachidonic acid, regulate immune homeostasis and inflammation via G protein-coupled receptors. Among them, thromboxane A2 (TXA2) primarily acts through its receptor TP to mediate platelet activation and vasoconstriction, but its roles in immune cells are increasingly recognized. Previous studies suggest that TP signaling influences T cell migration and DC–T cell interactions; however, its function in DCs during sepsis has not been systematically elucidated. S100a8/a9, a damage-associated molecular pattern (DAMP) protein secreted by myeloid cells, promotes neutrophil recruitment and activation through receptors such as TLR4 and contributes to various inflammatory diseases. Nevertheless, its precise cellular sources and regulatory mechanisms in sepsis remain unclear. This study focuses on TP signaling in DCs, revealing that it limits excessive neutrophil activation by suppressing S100a8/a9 expression, thereby providing new insights for precision immune intervention in sepsis.
Research Methods and Experiments
The researchers first analyzed publicly available single-cell RNA sequencing datasets to assess changes in immune cell subsets within peripheral blood mononuclear cells (PBMCs) from septic patients and to examine prostaglandin receptor expression in DCs. Subsequently, clinical samples were used to validate the relationship between TP expression in DCs and disease severity. For animal models, cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) challenge were employed to induce murine sepsis. By using DC-specific TP gene knockout mice (TPflox/floxCD11cCre), the impact of TP deletion on survival, inflammatory cytokines, lung injury, and neutrophil infiltration was evaluated. Single-cell RNA sequencing of splenic immune cells was performed to investigate how TP deficiency affects neutrophil proportions, and co-culture experiments of DCs with neutrophils were conducted to assess chemotactic capacity. Further analyses using gene expression profiling, RT-PCR, and Western blot confirmed upregulation of S100a8/a9 in TP-deficient DCs and validated this association in patient samples. Using S100a9 conditional knockout and S100a9/TP double-knockout mice, the essential role of S100a9 in the TP-deficient phenotype was established. Pharmacological interventions were carried out using the S100a8/a9 inhibitor paquinimod and the TLR4 inhibitor Resatorvid. SCENIC analysis and database predictions, combined with siRNA knockdown, Western blotting, and co-immunoprecipitation, were used to dissect the molecular mechanism by which TP regulates S100a8/a9. Finally, a DC-targeted nanodrug, DCpep-U-46619, was developed, and its therapeutic efficacy was assessed in the CLP model, including survival rates, inflammatory cytokines, neutrophil infiltration, and lung injury markers.Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to systematically reveal the protective role of the thromboxane receptor (TP) in dendritic cells during sepsis, expanding our understanding of prostaglandin signaling in innate immunity. Traditionally, the TXA2-TP pathway has been associated with platelet activation and thrombosis; however, this study uncovers its anti-inflammatory and immune homeostasis functions in DCs, suggesting tissue- and cell type-specific pleiotropic biological effects. This finding provides a novel mechanism for immune dysregulation in sepsis—namely, DC dysfunction driving pathological neutrophil activation via excessive S100a8/a9 release.
More importantly, the study proposes that targeted activation of TP receptors in DCs could serve as a therapeutic strategy, avoiding the side effects of systemic TP agonism. The developed nanodrug DCpep-U-46619 achieves cell-type-specific intervention, demonstrating the potential of precision immunotherapy. Future studies could further explore the application of TP agonists in other inflammatory diseases or develop more efficient targeted delivery systems. Additionally, the potential of S100a8/a9 as a biomarker warrants validation in clinical cohorts, possibly aiding in sepsis stratification and treatment response prediction.
Conclusion
This study systematically elucidates the immunomodulatory function and molecular mechanism of the thromboxane receptor (TP) in dendritic cells during sepsis. It demonstrates that TP expression is significantly reduced in DCs from both septic patients and animal models, and correlates negatively with disease severity. DC-specific deletion of TP exacerbates sepsis phenotypes, including higher mortality, stronger inflammatory responses, excessive neutrophil infiltration, and lung injury. Mechanistically, TP inhibits S100a8/a9 expression in DCs via activation of the PKCδ-Stat1 signaling pathway, thereby limiting neutrophil recruitment and activation. The S100a8/a9-TLR4 axis acts as a key downstream effector pathway of TP, and inhibition of this axis reverses the severe phenotypes caused by TP deficiency. The study further develops a DC-targeted nanodrug, DCpep-U-46619, which specifically activates TP in DCs and effectively alleviates sepsis symptoms and improves survival. These findings not only uncover a novel immunoregulatory role of TP in DCs but also provide new targets and strategies for precision treatment of sepsis, holding significant translational medical value.
