2. Academic Validation
  3. EGFR orchestrates neutrophil activation and NETosis via CEBPβ-dependent PGLYRP1 induction

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

  • Cell Death Differ. 2026 Jan 15. doi: 10.1038/s41418-026-01660-6.
Xiaolei Liu # 1,  Yue Lu # 1,  Yuanbo Guo # 2,  Guorong Huang 1,  Jiahui Li 1,  Jingran Lin 1,  Zhijie Li 3,  Liangqing Zhang 4,  Hanhui Zhong 5,  Yiwen Zhang 6,  Jing Tang 7
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
  • 2 Department of Anesthesiology, Guangdong Provincial People's Hospital (Guangdong Academy of Sciences), Southern Medical University, Guangzhou, China.
  • 3 Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China.
  • 4 Department of Anesthesiology, The Second Affiliated hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
  • 5 Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China. [email protected].
  • 6 Department of Anesthesiology,The Eighth Affiliated Hospital of Southern Medical University, Foshan, Guangdong, China. [email protected].
  • 7 Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China. [email protected].
  • # Contributed equally.
PMID: 41540251 DOI: 10.1038/s41418-026-01660-6
Abstract

Excessive neutrophil activation and neutrophil extracellular trap (NET) release drive systemic inflammation and organ injury in sepsis, yet the upstream regulatory pathways remain incompletely defined. Here, we identify epidermal growth factor receptor (EGFR) as a critical neutrophil-intrinsic regulator of NETosis. EGFR expression was markedly elevated in neutrophils from patients with sepsis and correlated with disease severity. Neutrophil-specific EGFR deletion in mice improved survival after polymicrobial sepsis by reducing cytokine storm, tissue injury, and NET formation. Mechanistically, EGFR associated with CCAAT/enhancer-binding protein beta (CEBPβ) and recruited Mitogen-activated protein kinase 14 (MAPK14) to phosphorylate CEBPβ, promoting its nuclear localization and transcriptional activation of peptidoglycan recognition protein 1 (PGLYRP1). Elevated PGLYRP1, in turn, amplified NETs release via autocrine engagement of triggering receptor expressed on myeloid cell-1 (TREM-1), establishing a feed-forward inflammatory loop. Administration of recombinant PGLYRP1 or forced CEBPβ overexpression reversed the protection conferred by EGFR deficiency, confirming the centrality of this axis. These findings define an unrecognized EGFR-MAPK14-CEBPβ-PGLYRP1-TREM1 circuit that links receptor signaling to pathological NETosis and highlight a promising therapeutic target to attenuate neutrophil-driven immunopathology in sepsis.

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