Growth differentiation factor 15 aggravates sepsis-induced cognitive and memory impairments by promoting microglial inflammatory responses and phagocytosis.

Summary

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.

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.

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.

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.