Daily Sepsis Research Analysis
Today's top sepsis research spans mechanistic discovery and clinically actionable risk stratification. AEC-II–derived exosomal lncRNA Rmrp was shown to drive alveolar macrophage immunosuppression, while endothelial Nur77 activation by cytosporone B corrected sepsis-induced coagulopathy via the thrombomodulin–APC axis. A nation-wide analysis validated the 2025 ISTH overt DIC score cutoffs for mortality risk across sepsis and malignancy cohorts.
Summary
Today's top sepsis research spans mechanistic discovery and clinically actionable risk stratification. AEC-II–derived exosomal lncRNA Rmrp was shown to drive alveolar macrophage immunosuppression, while endothelial Nur77 activation by cytosporone B corrected sepsis-induced coagulopathy via the thrombomodulin–APC axis. A nation-wide analysis validated the 2025 ISTH overt DIC score cutoffs for mortality risk across sepsis and malignancy cohorts.
Research Themes
- Exosomal long non-coding RNA mediates sepsis-induced immunometabolic paralysis in the lung
- Endothelial Nur77–thrombomodulin pathway as a therapeutic target for sepsis-induced coagulopathy
- External validation of 2025 ISTH overt DIC scoring for mortality risk stratification
Selected Articles
1. Type II Alveolar Epithelial Cells Promote Sepsis-Induced Immunosuppression in Alveolar Macrophages via Exosomal lncRNA Rmrp Release.
AEC-II-derived exosomal lncRNA Rmrp induces glycolytic failure and immune tolerance in alveolar macrophages after CLP sepsis by stabilizing ZFP36 and accelerating Pfkfb3 mRNA decay. Depletion of Rmrp in AEC-IIs or AMs mitigated SII and reduced secondary Pseudomonas pneumonia, and circulating exosomal Rmrp correlated with AM tolerance and patient prognosis.
Impact: This work reveals a previously unrecognized epithelial–macrophage exosomal lncRNA axis that mechanistically explains sepsis-induced immunosuppression and identifies a candidate biomarker/target.
Clinical Implications: Exosomal Rmrp could serve as a biomarker to identify patients at risk of sepsis-induced immunosuppression and secondary pneumonia, and targeting the Rmrp–ZFP36–Pfkfb3 axis may restore macrophage glycolysis and host defense.
Key Findings
- AEC-II exosomal Rmrp drives AM glycolytic defects and immune tolerance after CLP sepsis; cell-specific Rmrp depletion alleviates SII and reduces secondary Pseudomonas pneumonia.
- Rmrp stabilizes ZFP36 by inhibiting its ubiquitination, which accelerates Pfkfb3 mRNA decay and impairs glycolysis in AMs.
- Exosomal Rmrp levels correlate with AM immune tolerance and sepsis patient prognosis, suggesting biomarker utility.
Methodological Strengths
- In vivo CLP sepsis model with secondary Pseudomonas challenge and cell-specific Rmrp manipulation
- Mechanistic dissection linking exosomal lncRNA to ZFP36–Pfkfb3 metabolic control with patient correlation
Limitations
- Preclinical mouse model; human validation limited to correlative biomarker analyses
- Dosing, timing, and safety of potential interventions targeting this axis are untested clinically
Future Directions: Prospective clinical studies to validate exosomal Rmrp as a prognostic/predictive biomarker and development of strategies to modulate the Rmrp–ZFP36–Pfkfb3 axis to reverse SII.
Secondary pneumonia, a common complication of sepsis-induced immunosuppression (SII), is closely linked to alveolar macrophage (AM) dysfunction primarily due to impaired glycolytic activity. However, the underlying molecular mechanisms remain unclear. In this study, it is found that exosomal RNA component of the mitochondrial RNA processing endoribonuclease (Rmrp), derived from type II alveolar epithelial cells (AEC-IIs), drives glycolytic defects and immune tolerance in AMs following cecal ligation and puncture (CLP) sepsis. Targeted depletion of Rmrp in either AEC-IIs or AMs alleviated SII and secondary pneumonia induced by Pseudomonas aeruginosa infection 48 h post CLP. Mechanistically, Rmrp interacts with and inhibits the ubiquitination and degradation of the RNA-binding protein zinc finger protein 36 (ZFP36). This results in ZFP36 upregulation, subsequently accelerating the decay of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3) mRNA by binding to its AU-rich elements in the 3' untranslated region. The degradation of Pfkfb3 mRNA leads to impaired glycolysis and suppresses immune responses in AMs after sepsis. Additionally, it is found that exosomal Rmrp levels are correlated with AM immune tolerance and the prognosis of patients with sepsis. These findings highlight the critical role of AEC-II-derived exosomal Rmrp in the pathogenesis of SII and secondary pneumonia. Importantly, the study suggests that exosomal Rmrp may serve as a biomarker for predicting and managing SII in clinical settings.
2. Cytosporone B ameliorates hypercoagulability in sepsis by agonizing the Nur77-thrombomodulin pathway.
Cytosporone B activates endothelial Nur77 to upregulate thrombomodulin, enhancing APC generation and correcting hypercoagulability in CLP sepsis models. Effects include reduced procoagulant response, restoration of fibrinolysis, and inhibition of complement activation, dependent on endothelial Nur77.
Impact: Identifies a druggable endothelial transcriptional pathway (Nur77–TM–APC) that mechanistically rectifies sepsis-induced coagulopathy with multi-system readouts.
Clinical Implications: Nur77 agonism (e.g., cytosporone B analogs) could complement current supportive care by restoring endogenous TM–APC anticoagulant activity in early SIC; translational studies are warranted.
Key Findings
- Endothelial Nur77 is upregulated in sepsis; its knockout worsens organ injury and early coagulopathy after CLP.
- Cytosporone B attenuates TNF-α–induced procoagulant responses in HUVECs via the Nur77–thrombomodulin pathway.
- In vivo, Csn-B enhances TM–APC activation, restores fibrinolysis, and suppresses complement (C3/C5) activation, improving hypercoagulability in SIC in a Nur77-dependent manner.
Methodological Strengths
- Use of endothelial conditional Nur77 knockout mice to establish pathway causality
- Convergent in vitro (HUVEC) and in vivo (CLP) evidence across coagulation, fibrinolysis, and complement systems
Limitations
- Preclinical data; human pharmacokinetics, dosing, and safety of Nur77 agonism remain unknown
- Single-agent focus; interactions with standard anticoagulant or anti-inflammatory therapies not evaluated
Future Directions: Dose–response, toxicity, and pharmacology studies of Nur77 agonists, followed by early-phase clinical trials focusing on SIC endpoints and biomarker-guided patient selection.
BACKGROUND: Sepsis-induced coagulopathy (SIC) is often a sign of high mortality and poor prognosis in patients with sepsis. Thrombomodulin (TM) plays an important anticoagulant role by activating protein (AP)C. OBJECTIVES: Our previous study has shown that the overexpression of Nur77 upregulates TM expression in human umbilical vein endothelial cells (HUVECs). This study aimed to investigate whether upregulation of Nur77 using cytosporone (Csn)-B could ameliorate SIC. METHODS: A mouse model of SIC was prepared by cecum ligation and puncture (CLP) operation. Five hours after CLP, coagulation-related indicators and histopathologic injury of the liver, lungs, and kidneys were investigated. The effect of Csn-B on the clotting time of HUVECs transfected with Nur77 or TM small-interfering RNA in response to tumor necrosis factor α stimulation was observed. The effects of Csn-B on survival, organ damage, microthrombosis, coagulation factors, TM activated protein C anticoagulant system, fibrinolytic system, and complement system were observed in vascular endothelial conditional knockout Nur77 mice after CLP. RESULTS: Sepsis-induced upregulation of Nur77 in vascular endothelial cells. Knockout of Nur77 in vascular endothelium exacerbated organ damage and early coagulation dysfunction in sepsis. Csn-B attenuated the procoagulant response of HUVEC to tumor necrosis factor α stimulation, which is dependent on the activation of Nur77-TM pathway. Furthermore, Csn-B relied on activation of vascular endothelial Nur77 to inhibit the increase of coagulation factors, enhance activation of TM activated protein C, restore fibrinolysis homeostasis, and inhibit C3 and C5 activation to ameliorate hypercoagulability in SIC. CONCLUSION: Csn-B improves early coagulopathy in sepsis by increasing endogenous TM through upregulating Nur77 in the vascular endothelium.
3. Potential utility of the new ISTH overt disseminated intravascular coagulation scoring system for mortality risk assessment of patients with sepsis, hematopoietic neoplasms, and solid cancers: a nation-wide database study in Japan.
Using a nation-wide claims-laboratory database, the study demonstrates that the proposed 2025 ISTH overt DIC cutoffs (e.g., low fibrinogen, thrombocytopenia, prolonged PT, elevated fibrin-related markers) align with mortality risk patterns in sepsis, hematopoietic neoplasms, and solid cancers.
Impact: Provides early external validation of the 2025 ISTH overt DIC score across major clinical populations, supporting immediate uptake for risk stratification.
Clinical Implications: Clinicians can adopt the updated ISTH overt DIC thresholds to identify high-risk patients at admission and prioritize monitoring and interventions in sepsis and oncology settings.
Key Findings
- In a nation-wide Japanese database, mortality risk increased with low fibrinogen, thrombocytopenia, prolonged PT, and elevated fibrin-related markers at admission.
- Patterns were consistent across sepsis (n=8,181), hematopoietic neoplasms (n=7,548), and solid cancers (n=11,614), supporting the 2025 ISTH overt DIC scoring cutoffs.
- Restricted cubic spline modeling captured nonlinear relationships between coagulation parameters and in-hospital death.
Methodological Strengths
- Large, nation-wide cohort with standardized admission-day coagulation laboratories across disease groups
- Use of restricted cubic splines to model nonlinear risk relationships
Limitations
- Retrospective observational design susceptible to residual confounding and measurement bias
- Generalizability outside Japan and to settings without complete lab data may be limited
Future Directions: Prospective validation and calibration of the 2025 ISTH overt DIC score in diverse international cohorts and integration into sepsis triage pathways.
BACKGROUND: Disseminated intravascular coagulation (DIC) is characterized by systemic activation of coagulation pathways within the microvasculature, ultimately resulting in multiorgan dysfunction. The International Society on Thrombosis and Haemostasis (ISTH) subcommittee has recently introduced the 2025 overt DIC scoring system for clinical diagnosis. OBJECTIVES: This study aimed to evaluate the clinical relevance of the 2025 ISTH overt DIC scoring system and its proposed cutoff values for the mortality risk assessment in patients with diverse underlying diseases. METHODS: Patient data were extracted from the Japan Medical Data Center database, focusing on individuals diagnosed with sepsis, hematopoietic neoplasms, or solid cancers. Patients were included only if baseline levels of fibrinogen, platelets, prothrombin time (PT), and fibrin-related markers were available on the day of admission. Restricted cubic spline models were applied to evaluate nonlinear associations between coagulation parameters and in-hospital death. RESULTS: Data from 8181 patients with sepsis, 7548 patients with hematopoietic neoplasms, and 11 614 with solid cancers revealed a marked increase in mortality associated with fibrinogen < 2 g/L, platelets < 100 × 10 CONCLUSION: These findings support the prognostic utility of the 2025 ISTH overt DIC scoring system and its proposed cutoff values in evaluating mortality risk among patients with sepsis, hematopoietic malignancies, and solid cancers.