Dataset Information

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE315040 | GEO | 2026/01/05

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Sepsis is the most common cause of hospitalization worldwide. Millions of people survive sepsis each year and are at risk for rehospitalization and death. Pulmonary complications such as respiratory failure due to pneumonia and exacerbation of chronic respiratory disease are among the most common reasons for rehospitalization in sepsis survivors. In order to prevent additional morbidity and death in patients surviving sepsis, we must establish biomarkers to identify patients at risk for pulmonary complications and develop treatments. Late complications in sepsis survivors, particularly nosocomial infections, are proposed to occur through persistent immune reprogramming after sepsis known as immunoparalysis. However, pro-inflammatory immune reprogramming in the form of primed or enhanced responses to secondary stimuli has also been described and could directly contribute to tissue injury and death. Primed immune responses and their contribution to long-term sepsis complications remains understudied. We hypothesize that primed immune responses to inflammatory stimuli in the lung after sepsis are associated with pulmonary complications in survivors of sepsis. To this end, we developed a model of antibiotic treated sepsis induced by cecal ligation and puncture followed three weeks later by secondary challenge with intranasal lipopolysaccharide to induce inflammatory lung injury. We find that mice surviving sepsis have enhanced lung injury responses in the setting of an exaggerated proinflammatory immune response, including primed Ly6Chi monocyte Tnf expression. Using RNA sequencing, we identified derangements in lung gene expression after CLP prior to LPS administration which may mediate enhanced lung injury in this model. One potential mediator, S100A8/A9, was also found to be elevated in the circulation of human sepsis survivors for up to 180 days after sepsis. These findings validate our model and identify S100A8/A9 as one of many potential biomarkers and therapeutic targets for patients at risk for long-term pulmonary complications after sepsis. The role of S100A8/A9, monocyte priming, and other factors predisposing to enhanced lung injury responses and pulmonary complications after sepsis warrant further investigation in humans and mice.

Project description:Systemic juvenile idiopathic arthritis (SJIA) is a chronic childhood arthropathy with features of autoinflammation. Early inflammatory SJIA is associated with expansion and activation of neutrophils with a sepsis-like phenotype, but neutrophil phenotypes present in longstanding and clinically inactive disease (CID) are unknown. The objective of this study was to examine activated neutrophil subsets, S100 alarmin release, and gene expression signatures in children with a spectrum of SJIA disease activity. Methods: Highly-purified neutrophils were isolated using a two-step procedure of density-gradient centrifugation followed by magnetic-bead based negative selection prior to flow cytometry or cell culture to quantify S100 protein release. Whole transcriptome gene expression profiles were compared in neutrophils from children with both active SJIA and CID. Results: Patients with SJIA and active systemic features demonstrated a higher number of CD16+CD62Llo neutrophil population compared to controls. This neutrophil subset was not seen in patients with CID or patients with active arthritis not exhibiting systemic features. Using imaging flow cytometry, CD16+CD62Llo neutrophils from patients with active SJIA and features of macrophage activation syndrome (MAS) had increased nuclear hypersegmentation compared to CD16+CD62L+ neutrophils. Serum levels of S100A8/A9 and S100A12 were strongly correlated with peripheral blood neutrophil counts. Neutrophils from active SJIA patients did not show enhanced resting S100 protein release; however, regardless of disease activity, neutrophils from SJIA patients did show enhanced S100A8/A9 release upon PMA stimulation compared to control neutrophils. Furthermore, whole transcriptome analysis of highly purified neutrophils from children with active SJIA identified 214 differentially expressed genes compared to neutrophils from healthy controls. The most significantly upregulated gene pathway was Immune System Process, including AIM2, IL18RAP, and NLRC4. Interestingly, this gene set showed intermediate levels of expression in neutrophils from patients with long-standing CID yet persistent serum IL-18 elevation. Indeed, all patient samples regardless of disease activity demonstrated elevated inflammatory gene expression, including inflammasome components and S100A8. Conclusion: We identify features of neutrophil activation in SJIA patients with active disease and CID, including a proinflammatory gene expression signature, reflecting persistent innate immune activation. Taken together, these studies expand understanding of neutrophil function in chronic autoinflammatory disorders such as SJIA.

Dataset Information

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

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets