Brief intro:
- Author: Xiaolei Liu, Yue Lu, Yuanbo Guo, Guorong Huang, Jiahui Li, Jingran Lin, Zhijie Li, Liangqing Zhang, Hanhui Zhong, Yiwen Zhang & Jing Tang
- Journal: Cell Death & Differentiation
- Doi: https://www.doi.org/10.1038/s41418-026-01660-6
- Publication Date: 2026/1/15
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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