Growth differentiation factor 15 aggravates sepsis-induced cognitive and memory impairments by promoting microglial inflammatory responses and phagocytosis.
Summary
In LPS-induced murine sepsis, CSF GDF15 rose markedly; intracerebroventricular anti-GDF15 (ponsegromab) mitigated cognitive and memory deficits, reduced microglial activation/phagocytosis, and prevented synaptic loss. In vitro, GDF15 enhanced microglial inflammatory cytokines and phagocytic activity, supporting a causal role.
Key Findings
- CSF GDF15 levels increased significantly after LPS-induced sepsis in mice.
- Intracerebroventricular anti-GDF15 (ponsegromab) improved fear-conditioning and novel object recognition performance.
- GDF15 promoted microglial inflammatory cytokine production and phagocytosis; antibody treatment reduced microglial activation and protected synapses.
Clinical Implications
While preclinical, these data suggest GDF15 blockade could become a therapeutic strategy for sepsis-associated encephalopathy. Future clinical translation will need systemic delivery approaches, safety evaluation, and biomarker-guided patient selection.
Why It Matters
Identifies GDF15 as a mechanistic driver of neuroinflammation and cognitive impairment in sepsis and demonstrates target engagement with a therapeutic antibody, opening a translational pathway for SAE.
Limitations
- LPS model may not capture the full complexity of polymicrobial sepsis
- Intracerebroventricular delivery limits immediate clinical translatability; sample sizes not detailed in abstract
Future Directions
Evaluate systemic anti-GDF15 strategies, validate in polymicrobial sepsis models, define dosing windows, and assess interaction with sedation/analgesia regimens and long-term cognitive outcomes.
Study Information
- Study Type
- Basic/Mechanistic
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical animal and cell-based mechanistic evidence without clinical outcomes.
- Study Design
- OTHER