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.
Sepsis, a life-threatening inflammatory disorder characterized by multiorgan failure, arises from a dysregulated immune response to infection. Modulating macrophage polarization has emerged as a promising strategy to control sepsis-associated inflammation. The endogenous metabolite itaconate has shown anti-inflammatory potential by suppressing the stimulator of interferon genes (STING) pathway, but its efficacy is inhibited by hyperactive glycolysis, which sustains macrophage overactivation. Here, we revealed a critical crosstalk between the itaconate-STING axis and glycolysis in macrophage-mediated inflammation. Building on this interplay, we developed a novel nanoparticle LDO (lonidamine disulfide 4-octyl-itaconate), a self-assembled metabolic regulator integrating an itaconate derivative with the glycolysis inhibitor Lonidamine. By concurrently targeting glycolysis and STING pathways, LDO reprograms macrophages to restore balanced polarization. In sepsis models, LDO effectively attenuates CCL2-driven cytokine storms, alleviates acute lung injury, and significantly enhances survival via metabolic reprogramming. This study offers a cytokine-regulatory strategy rooted in immunometabolism, providing a foundation for the translational development of immune metabolite-based sepsis therapies.
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.
OBJECTIVE: Severe acute kidney injury (AKI) portends poor outcomes in pediatric sepsis. We evaluated the trajectory and prognostic utility of AKI biomarkers in pediatric septic shock using a subset of participants in the ongoing Pragmatic Pediatric Trial of Balanced vs. Normal Saline Fluid in Sepsis (PRoMPT BOLUS) trial, NCT04102371. We tested whether fluid volume is associated with persistent elevation of urine neutrophil gelatinase-associated lipocalin (Ur-NGAL). DESIGN: Prospective, non-prespecified cohort study within the PRoMPT BOLUS trial. SETTING: Three children's hospitals in the United States. PATIENTS: Four hundred seventy-eight patients aged 2 months to younger than 18 years old with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Ur-NGAL, kidney injury molecule-1, liver fatty acid binding protein, and interleukin-18 and plasma cystatin C were collected at presentation (T1), days 2-3 (T2), and before discharge/death (T3). At presentation, 418 (88%) had no or only stage 1 AKI and 60 (12%) had stage 2/3 AKI defined using Kidney Disease Improving Global Outcomes creatinine thresholds. All biomarkers were higher with stage 2/3 compared with no/stage 1 AKI at T1 and T2, but only cystatin C remained higher at T3. Among patients with no/stage 1 AKI at presentation, those with Ur-NGAL greater than or equal to 150 vs. less than 150 ng/mL had fewer hospital-free days (21 [interquartile range (IQR) 15-24] vs. 23 d [IQR 19-25], p = 0.05). After applying inverse probability treatment weighting to balance covariates, 14% of patients who received greater than 100 mL/kg within 48 hours had persistently elevated Ur-NGAL over time compared with 6% who received 40-100 mL/kg (odds ratio 2.7 [95% CI, 1.1-6.2]). Hospital-free days were no different across fluid volume groups. CONCLUSIONS: Although kidney injury biomarkers mirrored serum creatinine in children with septic shock, elevated Ur-NGAL identified a subset with subclinical AKI with fewer hospital-free days despite no/stage 1 AKI by creatinine. Children receiving greater than 100 mL/kg fluid had greater odds of early and persistently elevated Ur-NGAL, suggesting high fluid volumes may perpetuate initial kidney damage.
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.
Preterm neonates die at a significantly higher rate from sepsis than full-term neonates, attributable to their dysregulated immune response. In addition to tissue destruction caused directly by bacterial invasion, an overwhelming cytokine response by the immune cells to bacterial antigens also results in collateral damage. Sepsis leads to decreased gene expression of a critical transcription factor, Krüppel-like factor-2 (KLF2), a tonic repressor of myeloid cell activation. Using a murine model of myeloid-Klf2 deletion, we show that loss of KLF2 is associated with decreased survival after endotoxemia in a developmentally dependent manner, with increased mortality at postnatal day 4 (P4) compared to P12 pups. This survival is significantly increased by neutrophil depletion. P4 knockout pups have increased proinflammatory cytokine levels after endotoxemia compared to P4 controls or P12 pups, with significantly increased levels of IL-1β, a product of the activation of the NLRP3 inflammasome complex. Loss of myeloid-KLF2 at an earlier postnatal age leads to a greater increase in NLRP3 priming and activation and greater IL-1β release by BMNs. Inhibition of NLRP3 inflammasome activation by MCC950 significantly increased survival after endotoxemia in P4 pups. Transcriptomic analysis of bone marrow neutrophils showed that loss of myeloid-KLF2 is associated with gene enrichment of proinflammatory pathways in a developmentally dependent manner. These data suggest that targeting KLF2 could be a novel strategy to decrease the proinflammatory cytokine storm in neonatal sepsis and improve survival in neonates with sepsis.