Daily Sepsis Research Analysis
Three studies advance sepsis science across therapy, risk stratification, and neonatal pathophysiology. A self-assembled metabolic regulator nanoparticle concurrently targeting glycolysis and STING reprograms macrophages, mitigating cytokine storm in preclinical sepsis. A prospective pediatric cohort shows urine NGAL identifies subclinical AKI and links high fluid volumes to persistent kidney injury signals, while a mechanistic study reveals neutrophil KLF2 restrains NLRP3 inflammasome–driven le
Summary
Three studies advance sepsis science across therapy, risk stratification, and neonatal pathophysiology. A self-assembled metabolic regulator nanoparticle concurrently targeting glycolysis and STING reprograms macrophages, mitigating cytokine storm in preclinical sepsis. A prospective pediatric cohort shows urine NGAL identifies subclinical AKI and links high fluid volumes to persistent kidney injury signals, while a mechanistic study reveals neutrophil KLF2 restrains NLRP3 inflammasome–driven lethality in neonatal endotoxemia.
Research Themes
- Immunometabolic modulation to control sepsis cytokine storm
- Biomarker-guided kidney risk and fluid stewardship in pediatric septic shock
- Developmental immunology and inflammasome signaling in neonatal sepsis
Selected Articles
1. A Self-Assembled Metabolic Regulator Reprograms Macrophages to Combat Cytokine Storm and Boost Sepsis Immunotherapy.
This preclinical study identifies crosstalk between the itaconate–STING axis and glycolysis in macrophage inflammation and introduces a self-assembled nanoparticle (LDO) that co-targets both pathways. LDO reprograms macrophage polarization, reduces CCL2-driven cytokine storms, ameliorates acute lung injury, and improves survival in sepsis models.
Impact: Provides a novel immunometabolic strategy that could shift sepsis therapy from nonspecific suppression to targeted macrophage reprogramming. The dual-pathway design may inspire translational development of combination metabolic-immunomodulators.
Clinical Implications: Although preclinical, the work supports developing dual-target immunometabolic agents for sepsis. If safety and pharmacokinetics are favorable, such agents could complement antimicrobial and organ support by damping cytokine storm without broad immunosuppression.
Key Findings
- Discovered functional crosstalk between the itaconate–STING axis and glycolysis in macrophage-mediated inflammation.
- Engineered a self-assembled nanoparticle (LDO) combining 4-octyl-itaconate with lonidamine to co-target STING signaling and glycolysis.
- In murine sepsis models, LDO attenuated CCL2-driven cytokine storms, reduced acute lung injury, and significantly improved survival.
Methodological Strengths
- Rational design grounded in mechanistic crosstalk between metabolic and innate immune pathways.
- Demonstrated in vivo efficacy across sepsis models with survival and organ injury endpoints.
Limitations
- Preclinical animal data; human safety, pharmacokinetics, and efficacy are unknown.
- Sepsis models may not capture the heterogeneity and comorbidities of human sepsis.
Future Directions: Conduct dose-ranging, toxicology, and pharmacokinetic studies; assess efficacy in polymicrobial sepsis and immunocompromised models; explore combination with antibiotics and organ support; evaluate biomarkers of response.
2. Time Course of Kidney Injury Biomarkers in Children With Septic Shock: Nested Cohort Study Within the Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis Trial.
In 478 children with septic shock, kidney injury biomarkers tracked AKI severity early, but only cystatin C remained elevated near discharge. Elevated urine NGAL identified subclinical AKI with fewer hospital-free days even when creatinine-based AKI was absent/mild. Receiving >100 mL/kg fluids in 48 hours doubled the odds of persistently elevated urine NGAL.
Impact: Supports biomarker-guided risk stratification in pediatric septic shock and highlights potential harm of high-volume resuscitation on renal injury signals.
Clinical Implications: Consider integrating urine NGAL and cystatin C to detect subclinical AKI and guide fluid stewardship. Avoid exceeding >100 mL/kg within 48 hours when possible, pending RCT validation, and monitor kidney biomarkers for early injury.
Key Findings
- All measured kidney injury biomarkers were higher with KDIGO stage 2/3 vs. no/stage 1 AKI at presentation and days 2–3.
- Only plasma cystatin C remained elevated prior to discharge/death (T3).
- Among children without/mild AKI at presentation, urine NGAL ≥150 ng/mL identified subclinical AKI and fewer hospital-free days.
- Fluid >100 mL/kg in 48 hours was associated with persistently elevated urine NGAL (IPTW-adjusted OR 2.7; 95% CI 1.1–6.2).
Methodological Strengths
- Prospective multicenter cohort nested within an ongoing pragmatic RCT infrastructure.
- Serial biomarker measurements and use of inverse probability treatment weighting to address confounding by fluid volume.
Limitations
- Non-prespecified biomarker substudy; potential selection bias across three centers.
- No long-term kidney outcomes; creatinine-based AKI definition may miss tubular injury.
Future Directions: Randomized trials of biomarker-guided fluid strategies; validation of urine NGAL thresholds; integration with EHR alerts to prevent fluid-associated kidney injury.
3. Neutrophil KLF2 regulates inflammasome-dependent neonatal mortality from endotoxemia.
Myeloid KLF2 restrains inflammasome-driven cytokine responses in neonatal endotoxemia. KLF2 loss increases IL-1β via NLRP3, worsens survival especially at postnatal day 4, and survival is rescued by NLRP3 inhibition or neutrophil depletion, highlighting developmental regulation of neutrophil inflammatory programming.
Impact: Reveals a mechanistic, developmentally regulated brake on neonatal hyperinflammation with actionable targets (KLF2/NLRP3) for sepsis therapy.
Clinical Implications: While mechanistic, the data support exploring NLRP3 inhibitors and approaches to preserve or augment KLF2 signaling in neonatal sepsis. Translation requires safety evaluation in neonates.
Key Findings
- Myeloid-specific Klf2 deletion reduced survival after endotoxemia, with greater mortality at postnatal day 4 than at day 12.
- KLF2 loss increased IL-1β via NLRP3 inflammasome activation; neutrophil depletion improved survival.
- Pharmacologic inhibition of NLRP3 with MCC950 significantly improved survival in P4 pups.
- Transcriptomics of bone marrow neutrophils showed proinflammatory pathway enrichment with KLF2 loss in a developmentally dependent manner.
Methodological Strengths
- Genetic knockout model combined with pharmacologic rescue (MCC950) and neutrophil depletion.
- Developmental comparison (P4 vs. P12) with transcriptomic profiling to elucidate mechanisms.
Limitations
- Endotoxemia model may not fully recapitulate polymicrobial neonatal sepsis.
- Translation to human neonates is uncertain and requires safety/efficacy trials.
Future Directions: Evaluate KLF2-modulating strategies and clinically relevant NLRP3 inhibitors in neonatal polymicrobial sepsis models; assess interactions with antibiotics and supportive care.