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

Summary

This mechanistic study identifies EGFR as a neutrophil-intrinsic master regulator of pathological NETosis in sepsis via a MAPK14–CEBPβ–PGLYRP1–TREM‑1 circuit. Genetic ablation of EGFR in neutrophils reduced NETs, cytokine storm, tissue injury, and improved survival in polymicrobial sepsis; rescue experiments validated pathway centrality.

Key Findings

• EGFR expression is elevated in sepsis patient neutrophils and correlates with disease severity.
• Neutrophil-specific EGFR deletion improves survival and reduces NETs, cytokines, and tissue injury in polymicrobial sepsis.
• EGFR recruits MAPK14 to phosphorylate CEBPβ, driving PGLYRP1 transcription and NETosis via autocrine TREM‑1 signaling.
• Recombinant PGLYRP1 or CEBPβ overexpression reverses the protection in EGFR-deficient neutrophils, confirming pathway centrality.

Clinical Implications

Therapeutic targeting of EGFR or downstream nodes (PGLYRP1, TREM‑1) could attenuate NETosis and systemic inflammation in sepsis. Findings support exploration of repurposing EGFR inhibitors or TREM‑1 antagonists with careful safety evaluation.

Limitations

• Preclinical study without interventional human trials; translational efficacy and safety remain untested.
• Potential class-specific toxicities of EGFR inhibition in sepsis contexts were not evaluated.

Future Directions

Evaluate pharmacologic modulation of the EGFR–PGLYRP1–TREM‑1 axis in large-animal sepsis models and early-phase human studies; assess combination strategies with antimicrobial and organ support therapies.