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

Summary

This mechanistic study identifies EGFR as a neutrophil-intrinsic driver of NETosis in sepsis via an EGFR–MAPK14–CEBPβ–PGLYRP1–TREM1 axis. Neutrophil-specific EGFR deletion improves survival and reduces cytokine storm and NETs; rescue with recombinant PGLYRP1 confirms pathway centrality.

Key Findings

• EGFR is upregulated in neutrophils from sepsis patients and correlates with disease severity.
• Neutrophil-specific EGFR knockout improves survival and reduces cytokine storm, tissue injury, and NET formation in polymicrobial sepsis.
• EGFR recruits MAPK14 to phosphorylate CEBPβ, driving PGLYRP1 transcription; PGLYRP1 amplifies NETosis via autocrine TREM-1 signaling.
• Recombinant PGLYRP1 or CEBPβ overexpression reverses the protective effects of EGFR deletion, confirming pathway centrality.

Clinical Implications

Supports exploration of EGFR or TREM-1/PGLYRP1–axis inhibitors as adjuncts in severe sepsis to reduce NETosis and immunopathology; may refine patient stratification using neutrophil EGFR expression.

Limitations

• Preclinical mouse models may not fully recapitulate human sepsis heterogeneity.
• Potential off-target or immunosuppressive effects of EGFR/MAPK14 pathway inhibition require careful evaluation.

Future Directions

Test pharmacologic EGFR, MAPK14, or TREM-1/PGLYRP1 inhibitors in sepsis models with comorbidities; validate neutrophil EGFR/CEBPβ/PGLYRP1 signatures as biomarkers; design early-phase clinical trials targeting this axis.