EGFR orchestrates neutrophil activation and NETosis via CEBPβ-dependent PGLYRP1 induction.

Summary

This study uncovers a neutrophil-intrinsic EGFR–MAPK14–CEBPβ–PGLYRP1–TREM1 pathway that drives NETosis and worsens sepsis, with genetic EGFR deletion improving survival and reducing NETs and tissue injury. Rescue experiments confirm axis centrality, positioning EGFR or downstream nodes as therapeutic targets to mitigate neutrophil-driven immunopathology.

Key Findings

• EGFR is upregulated in septic patient neutrophils and correlates with disease severity.
• Neutrophil-specific EGFR deletion improves survival and reduces NET formation, cytokine storm, and tissue injury in polymicrobial sepsis.
• EGFR recruits MAPK14 to phosphorylate CEBPβ, inducing PGLYRP1 transcription; PGLYRP1 amplifies NETosis via autocrine TREM-1 signaling.
• Recombinant PGLYRP1 or enforced CEBPβ expression reverses protection in EGFR-deficient neutrophils, confirming pathway centrality.

Clinical Implications

Targeting EGFR signaling or the PGLYRP1–TREM1 loop could attenuate NETosis, cytokine storm, and organ injury in sepsis; translational studies and early-phase trials should assess safety/efficacy in critically ill patients.

Limitations

• Preclinical findings require validation with pharmacologic inhibitors and in large animal models.
• Potential off-target effects and safety of targeting EGFR/TREM-1 pathways in sepsis remain unknown.

Future Directions

Evaluate selective EGFR–MAPK14–CEBPβ–PGLYRP1–TREM1 axis inhibitors in translational models; develop biomarkers (e.g., neutrophil EGFR/PGLYRP1) to stratify patients for anti-NETosis therapies.