Daily Sepsis Research Analysis
Three mechanistic studies reshape our understanding of sepsis pathobiology: a randomized porcine model shows severity-dependent, early renal mitochondrial dysfunction preceding macro-hemodynamic changes; GDF15 drives microglial activation and cognitive deficits in sepsis-associated encephalopathy, reversible with an anti-GDF15 antibody; and bacteria exploit APE1 downregulation to blunt macrophage phagocytosis via GSK3β–NRF2 signaling. These works nominate mitochondrial dynamics, GDF15, and the A
Summary
Three mechanistic studies reshape our understanding of sepsis pathobiology: a randomized porcine model shows severity-dependent, early renal mitochondrial dysfunction preceding macro-hemodynamic changes; GDF15 drives microglial activation and cognitive deficits in sepsis-associated encephalopathy, reversible with an anti-GDF15 antibody; and bacteria exploit APE1 downregulation to blunt macrophage phagocytosis via GSK3β–NRF2 signaling. These works nominate mitochondrial dynamics, GDF15, and the APE1/NRF2 axis as actionable targets.
Research Themes
- Sepsis-induced organ dysfunction and mitochondrial pathobiology
- Neuroinflammation and cognitive impairment in sepsis-associated encephalopathy
- Innate immune evasion via APE1/NRF2 signaling in macrophages
Selected Articles
1. Renal mitochondria response to sepsis: a sequential biopsy evaluation of experimental porcine model.
In a randomized porcine fecal peritonitis model with sequential renal biopsies, high-severity sepsis caused an early decrease in oxidative phosphorylation and increased uncoupling that preceded macro-hemodynamic changes and coincided with rises in serum creatinine. Renal medulla exhibited lower mitochondrial capacity than cortex, and PGC-1α was reduced in high-severity animals. These data suggest severity-dependent mitochondrial endotypes in sepsis-induced AKI.
Impact: This large-animal, sequential tissue study reconciles conflicting preclinical findings by showing early, severity-dependent mitochondrial dysfunction that is independent of macro-hemodynamics, reframing SA-AKI mechanisms.
Clinical Implications: Renal dysfunction in severe sepsis may be driven by early mitochondrial failure rather than macro-hemodynamics, supporting early mitochondrial-targeted diagnostics and therapies (e.g., biogenesis enhancers) and suggesting phenotype-specific trial designs for SA-AKI.
Key Findings
- High-severity sepsis caused decreased oxidative phosphorylation and increased uncoupling within 24 hours, preceding renal macro-hemodynamic changes.
- Serum creatinine rose early, indicating renal dysfunction not primarily driven by hemodynamics.
- Renal medulla had lower oxidative phosphorylation and ETS activity than cortex; PGC-1α decreased in high-severity animals.
Methodological Strengths
- Randomized large-animal model with invasive instrumentation and sequential renal biopsies
- Integrated functional oxygraphy with protein markers of mitochondrial biogenesis/degradation
Limitations
- Small sample size (n=15) and open-label design in a single preclinical model
- Short observation window (~24 h) limits assessment of longer-term renal recovery or fibrosis
Future Directions: Define SA-AKI mitochondrial endotypes prospectively in humans, test mitochondrial biogenesis/uncoupling modulators, and integrate renal regional oxygenation imaging with bioenergetic biomarkers.
2. Growth differentiation factor 15 aggravates sepsis-induced cognitive and memory impairments by promoting microglial inflammatory responses and phagocytosis.
In an LPS-induced sepsis model, GDF15 levels rose in cerebrospinal fluid. Intracerebroventricular anti-GDF15 (ponsegromab) mitigated microglial activation and phagocytosis, protected synapses, and improved cognitive and memory performance. GDF15 emerges as a driver and therapeutic target in SAE.
Impact: Identifies GDF15 as a mechanistic driver of neuroinflammation and cognitive injury in sepsis with pharmacologic reversibility, opening translational avenues for targeted therapy in SAE.
Clinical Implications: If validated in humans, peripheral anti-GDF15 strategies or modulators of GDF15 signaling could be evaluated to prevent or treat SAE; early identification of patients with elevated GDF15 might guide neuroprotective interventions and post-ICU cognitive screening.
Key Findings
- CSF GDF15 levels were markedly elevated after LPS-induced sepsis.
- Anti-GDF15 antibody (ponsegromab) reduced microglial activation and phagocytosis in hippocampus and improved cognitive/memory outcomes.
- Synaptic loss was attenuated by GDF15 blockade, linking microglial phagocytosis to cognitive deficits.
Methodological Strengths
- In vivo and in vitro convergence with behavioral assays, immunohistochemistry, and transcriptomics
- Target validation using a monoclonal antibody against GDF15
Limitations
- LPS model may not capture full clinical heterogeneity of sepsis; intracerebroventricular delivery limits translational immediacy
- Sample sizes and long-term cognitive trajectories were not detailed
Future Directions: Test peripheral GDF15 blockade or pathway modulation in polymicrobial sepsis models, establish dose–response and timing, and develop blood/CSF biomarkers to enrich patients for future clinical trials.
3. Bacteria escape macrophage-mediated phagocytosis via targeting apurinic/apyrimidinic endonuclease 1 in sepsis.
APE1 expression is downregulated in macrophages during sepsis; its deficiency impairs phagocytosis of beads and E. coli and increases mortality in septic mice. Mechanistically, APE1 loss activates GSK3β, promoting NRF2 ubiquitination and degradation, reducing phagocytic receptor expression. Targeting the APE1/NRF2 axis may restore macrophage function.
Impact: Reveals a previously unappreciated APE1–GSK3β–NRF2 pathway controlling macrophage phagocytosis in sepsis, providing a mechanistic basis for NRF2 activation or GSK3β inhibition strategies.
Clinical Implications: Pharmacologic NRF2 activators or GSK3β inhibitors, or approaches that preserve APE1 function, could enhance macrophage bacterial clearance in sepsis; careful evaluation is needed to balance antimicrobial defense with inflammation.
Key Findings
- APE1 expression is downregulated in macrophages in vitro and in vivo during sepsis; APE1 deficiency increases mortality in septic mice.
- Reduced APE1 impairs macrophage phagocytosis of fluorescent beads and E. coli.
- APE1 loss activates GSK3β, driving NRF2 ubiquitination and proteasomal degradation, decreasing phagocytic receptor expression; APE1 redox function contributes.
Methodological Strengths
- Mechanistic dissection across in vitro and in vivo sepsis models with functional phagocytosis assays
- Pathway mapping linking APE1 to GSK3β activation and NRF2 degradation
Limitations
- Translational relevance uncertain without pharmacologic rescue in clinically relevant sepsis models
- Details of human validation or clinical samples are not reported
Future Directions: Test NRF2 activators, GSK3β inhibitors, or APE1-stabilizing strategies in polymicrobial sepsis models and evaluate host defense and inflammatory balance; assess APE1/NRF2 biomarkers in patients.