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.
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.
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.