Weekly Sepsis Research Analysis
This week’s sepsis literature highlights mechanistic advances that reshape our view of host responses and identify tractable therapeutic targets, alongside translational repurposing and preclinical delivery platforms. Key findings include coordinated NF-κB/chromatin–mediated macrophage memory, endothelial GSDMD as a driver of vascular injury (and a druggable target), and an IL-10–dependent immunometabolic protective effect of fluoxetine with translational potential. Parallel work advances nanome
Summary
This week’s sepsis literature highlights mechanistic advances that reshape our view of host responses and identify tractable therapeutic targets, alongside translational repurposing and preclinical delivery platforms. Key findings include coordinated NF-κB/chromatin–mediated macrophage memory, endothelial GSDMD as a driver of vascular injury (and a druggable target), and an IL-10–dependent immunometabolic protective effect of fluoxetine with translational potential. Parallel work advances nanomedicine delivery and early biomarker/diagnostic models that could accelerate risk stratification and precision therapy.
Selected Articles
1. Fluoxetine promotes IL-10-dependent metabolic defenses to protect from sepsis-induced lethality.
Preclinical mechanistic work shows fluoxetine elevates circulating IL-10 (independent of peripheral serotonin) and prevents sepsis-induced hypertriglyceridemia and cardiac metabolic dysfunction, thereby reducing lethality in animal models. The study links immunologic and metabolic endpoints and defines an actionable host-directed mechanism for repurposing a widely used SSRI.
Impact: Reveals a clear, testable IL-10–mediated immunometabolic mechanism linking an approved drug to sepsis protection, enabling rapid translation to controlled clinical trials.
Clinical Implications: Does not warrant immediate clinical adoption, but justifies phase 2 trials of fluoxetine as adjunctive therapy in sepsis with prespecified IL-10 and cardiometabolic endpoints and careful safety monitoring.
Key Findings
- Fluoxetine increases circulating IL-10 independent of peripheral serotonin.
- IL-10 is necessary to prevent sepsis-induced hypertriglyceridemia and cardiac metabolic dysfunction, reducing lethality.
2. Macrophage memory emerges from coordinated transcription factor and chromatin dynamics.
Using live-cell imaging, ATAC-seq, transcriptomics, deep learning, and an in vivo sepsis model, this study demonstrates that sequential inflammatory signals reprogram NF-κB networks and chromatin accessibility to encode macrophage memory at single-cell resolution. The work provides mechanistic principles (timing, TF–chromatin coordination) that could inform timing and targets for immunomodulatory interventions in sepsis.
Impact: Reframes innate immune memory in sepsis as an emergent TF–chromatin property and identifies mechanistic readouts that can be translated into biomarkers or timed epigenetic/immunomodulatory strategies.
Clinical Implications: Motivates development of assays that report macrophage TF/chromatin states for endotyping and for timing anti-inflammatory or epigenetic therapies in sepsis; long-term translation will require biomarker simplification for clinical use.
Key Findings
- Sequential inflammatory stimuli reprogram NF-κB networks and chromatin accessibility to create macrophage memory.
- Single-cell live imaging and ATAC-seq demonstrate memory encoding; deep learning links TF–chromatin dynamics to response tuning.
3. Endothelial GSDMD underlies LPS-induced systemic vascular injury and lethality.
Cell type–specific mouse models show endothelial (not myeloid) GSDMD mediates systemic vascular injury and lethality in endotoxemia/sepsis via a hepatocyte GSDMD–HMGB1–RAGE axis. A peptide inhibitor of endothelial GSDMD reduced endothelial damage and improved survival in vivo, indicating druggability of this pathway.
Impact: Identifies and pharmacologically validates endothelial GSDMD as a central, druggable mediator of sepsis-associated vascular failure—a direct translational target for adjunctive therapy in septic shock.
Clinical Implications: Supports development of endothelial-targeted GSDMD inhibitors and HMGB1–RAGE modulators for septic shock; prompts biomarker efforts for endothelial pyroptosis to stratify patients for such therapies.
Key Findings
- Endothelial-specific Gsdmd deletion protects against vascular injury and death in LPS/sepsis models; myeloid deletion does not.
- Hepatocyte GSDMD–mediated HMGB1 release activates endothelial RAGE driving systemic vascular injury.
- A polypeptide inhibitor of endothelial GSDMD attenuated damage and improved survival in vivo.