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

Summary

This mechanistic study shows that neutrophil-intrinsic EGFR signaling drives NETosis through a MAPK14-assisted activation of CEBPβ, which induces PGLYRP1 to amplify TREM-1 signaling. Neutrophil-specific EGFR deletion reduces NETs, cytokine storm, and mortality in murine polymicrobial sepsis; rescue experiments confirm pathway centrality.

Key Findings

• EGFR expression is elevated in neutrophils from sepsis patients and correlates with disease severity.
• Neutrophil-specific EGFR deletion improves survival and reduces cytokine storm, tissue injury, and NET formation in polymicrobial sepsis.
• EGFR recruits MAPK14 to phosphorylate CEBPβ, promoting nuclear localization and transcriptional activation of PGLYRP1.
• PGLYRP1 amplifies NET release via autocrine TREM-1 engagement, creating a feed-forward inflammatory loop.
• Recombinant PGLYRP1 or forced CEBPβ overexpression reverses the protection conferred by EGFR deficiency.

Clinical Implications

Supports exploration of EGFR pathway modulation (or downstream PGLYRP1/TREM-1 blockade) to attenuate neutrophil-driven immunopathology in sepsis. May inform biomarker-guided stratification of patients with elevated neutrophil EGFR.

Limitations

• Preclinical mouse models may not fully recapitulate human sepsis heterogeneity
• Safety and off-target effects of EGFR or PGLYRP1/TREM-1 modulation in infection require evaluation

Future Directions

Test pharmacologic EGFR, PGLYRP1, or TREM-1 inhibitors in diverse sepsis models and assess predictive biomarkers (neutrophil EGFR/CEBPβ/PGLYRP1) for patient stratification.