FOLR3+neutrophils contribute to sepsis by exacerbating hyper-inflammation.

Summary

Integrated single-cell and bulk transcriptomics identified a terminally differentiated, hyper-inflammatory FOLR3+ neutrophil subset enriched in non-survivors. Computational and experimental data implicate HIF-1A as a key driver, with FOLR3+ neutrophils recruiting platelets and secreting pro-inflammatory cytokines; higher FOLR3+ levels correlated with 28-day mortality.

Key Findings

• Five neutrophil clusters were identified; FOLR3+ neutrophils were predominant, terminally differentiated, hyper-inflammatory, and exhibited low HLA expression, especially in non-survivors.
• CellChat analysis suggested FOLR3+ neutrophils promote sepsis progression via platelet recruitment through RETN–CAP1 and NAMPT–ITGB1 signaling axes.
• External validation associated higher proportions of FOLR3+ neutrophils with increased 28-day mortality in sepsis.
• HIF-1A emerged as the key transcriptional driver; manipulating HIF-1A in human/mouse neutrophils altered FOLR3 expression and secretion of IL-1β, TNF-α, IL-8, and IL-6.

Clinical Implications

While not yet practice-changing, FOLR3+ neutrophils may evolve into a prognostic biomarker and therapeutic target; assays quantifying this subset could aid risk stratification and inform trials of HIF-1A/FOLR3-pathway modulation.

Limitations

• Primarily observational transcriptomic data; causal pathways in vivo remain to be confirmed
• Generalizability and standardization of FOLR3+ neutrophil quantification for clinical use are not established

Future Directions

Prospective, multicenter validation of FOLR3+ neutrophils as a prognostic biomarker; interventional studies targeting HIF-1A/FOLR3+ pathways to modulate hyper-inflammation in sepsis.