Daily Sepsis Research Analysis
Three papers advance sepsis science across mechanisms, biomarkers, and therapeutics. A JCI study identifies DLL4+ neutrophils driving endothelial PANoptosis via Notch1 and introduces a peptide inhibitor that improves outcomes in sepsis models. Complementing this, a JTH study links IFNβ to early DIC risk and uncovers a MALAT1–caspase-11 pathway for immunothrombosis, while a Journal of Controlled Release study demonstrates macrophage membrane-coated siRNA nanocomplexes that silence FEN1 to quell m
Summary
Three papers advance sepsis science across mechanisms, biomarkers, and therapeutics. A JCI study identifies DLL4+ neutrophils driving endothelial PANoptosis via Notch1 and introduces a peptide inhibitor that improves outcomes in sepsis models. Complementing this, a JTH study links IFNβ to early DIC risk and uncovers a MALAT1–caspase-11 pathway for immunothrombosis, while a Journal of Controlled Release study demonstrates macrophage membrane-coated siRNA nanocomplexes that silence FEN1 to quell mtDNA-driven cytokine storm.
Research Themes
- Endothelial injury and PANoptosis in sepsis-induced acute lung injury
- Immunothrombosis and early prediction of DIC via IFNβ–MALAT1–caspase-11 axis
- Biomimetic siRNA nanotherapeutics targeting mtDNA-driven inflammation
Selected Articles
1. DLL4+ neutrophils promote Notch1-mediated endothelial PANoptosis to exacerbate acute lung injury in sepsis.
This mechanistic study identifies a DLL4+ neutrophil subset that engages endothelial Notch1 to induce ZBP1-driven PANoptosis, worsening sepsis-induced ALI. A novel Notch1-DLL4 inhibitor peptide reduced endothelial PANoptosis, lung injury, permeability, inflammatory markers, and improved survival in sepsis models, highlighting a druggable axis.
Impact: Reveals a previously unrecognized neutrophil–endothelial pathway driving ALI and demonstrates a first-in-class inhibitor that improves outcomes in preclinical sepsis.
Clinical Implications: Targeting the Notch1–DLL4 interaction may prevent or mitigate sepsis-associated acute lung injury. If translated, NDI-like agents could complement current supportive care by preserving endothelial barrier function.
Key Findings
- eCIRP induces DLL4+ neutrophils that trigger ZBP1-mediated endothelial PANoptosis.
- DLL4 binds endothelial Notch1, activating Notch1 intracellular domain to amplify PANoptosis markers (cleaved GSDMD, cleaved caspase-3, p-MLKL).
- A Notch1-derived inhibitor (NDI) blocks DLL4–Notch1 interaction, reducing endothelial PANoptosis, lung injury, permeability, inflammatory markers, and improving survival in sepsis models.
Methodological Strengths
- Multi-system validation including in vitro endothelial assays and in vivo sepsis models.
- Mechanistic dissection of Notch1–DLL4 signaling with a rationally designed inhibitory peptide demonstrating functional rescue.
Limitations
- Preclinical models; human validation of DLL4+ neutrophils and NDI efficacy/safety is lacking.
- Potential off-target effects of Notch pathway modulation require careful evaluation.
Future Directions: Validate DLL4+ neutrophils and PANoptosis signatures in human sepsis cohorts; optimize NDI pharmacology, safety, and delivery; explore combination with standard sepsis care.
2. A Critical Role for MALAT1 in Gram-negative Bacteria-induced Coagulation via Regulation of Caspase-11 signaling.
Plasma IFNβ at admission predicts 48-hour DIC onset in sepsis, and mechanistic experiments show IFNβ induces macrophage MALAT1, which suppresses GPX4 and promotes caspase-11–dependent immunocoagulation. Macrophage-specific Malat1 deletion restores GPX4 activity, reduces LPS internalization and caspase-11 activation, and protects against coagulation.
Impact: Bridges clinical prediction (IFNβ) with a novel MALAT1–caspase-11 mechanism of sepsis-associated DIC, nominating actionable biomarkers and targets.
Clinical Implications: IFNβ measurement may aid early DIC risk stratification in sepsis, and therapeutically targeting MALAT1 or restoring GPX4 activity could mitigate immunothrombosis.
Key Findings
- Admission plasma IFNβ correlates with 48-hour onset of septic DIC, whereas HMGB1 does not.
- IFNβ induces macrophage MALAT1, which suppresses GPX4 via YY1/Hba-a1, enhancing LPS internalization and caspase-11 activation.
- Macrophage Malat1 deletion limits caspase-11/GSDMD-dependent PS exposure and protects against bacteria-induced coagulation.
Methodological Strengths
- Combined human biomarker assessment with leukocyte transcriptomics and gene-modified mouse models.
- Mechanistic validation across redox (GSH/GPX4), innate sensing (caspase-11), and membrane PS exposure readouts.
Limitations
- Clinical cohort size and external validation are not specified; predictive thresholds were not provided.
- Translational therapeutics (e.g., MALAT1 targeting) remain untested in humans.
Future Directions: Define IFNβ thresholds for DIC prediction in multi-center cohorts; develop MALAT1/GPX4-modulating therapies and assess safety/efficacy in preclinical large animals.
3. Biomimetic siRNA therapeutics attenuate mitochondrial DNA damage and cytokine storm in sepsis.
A macrophage membrane–cloaked nanocomplex delivers siFEN1 to macrophages, silencing FEN1 to prevent oxidized mtDNA fragmentation and leakage that drives NLRP3, cGAS-STING, and TLR9 pathways. In CLP sepsis, this biomimetic platform prolongs circulation, homes to inflamed tissues, restores immune homeostasis, and attenuates cytokine storm and organ failure.
Impact: Introduces a biomimetic siRNA delivery strategy targeting a central mtDNA-driven inflammatory amplifier (FEN1), offering a mechanistically precise avenue to modulate cytokine storm in sepsis.
Clinical Implications: While preclinical, macrophage-targeted siRNA against FEN1 represents a promising adjunct to blunt hyperinflammation and organ dysfunction; it motivates translational studies on safety, dosing, and timing in severe sepsis.
Key Findings
- FEN1 cleaves oxidized mtDNA into proinflammatory fragments that activate NLRP3, cGAS-STING, and TLR9 pathways in sepsis.
- Macrophage membrane–coated nanocomplexes efficiently deliver siFEN1 to macrophages, achieving robust FEN1 silencing in vivo.
- In CLP mice, siFEN1 nanocomplexes prolong circulation, home to inflamed tissues, reduce mtDNA fragmentation/leakage, restore immune homeostasis, and attenuate cytokine storm and organ failure.
Methodological Strengths
- Rational nanocarrier design with partial membrane cloaking to balance stability and macrophage uptake.
- In vivo functional validation in CLP sepsis with mechanistic readouts (mtDNA integrity, innate immune pathways, organ dysfunction).
Limitations
- Preclinical murine data; human pharmacokinetics, immunogenicity, and off-target effects are unknown.
- Manufacturing scalability and reproducibility of membrane-cloaked nanocomplexes need demonstration.
Future Directions: Assess safety, biodistribution, and efficacy in large-animal sepsis models; optimize dosing/timing; explore combination with antimicrobials and organ support strategies.