RRC ID 78858
Author Isono T, Hirayama S, Domon H, Maekawa T, Tamura H, Hiyoshi T, Sirisereephap K, Takenaka S, Noiri Y, Terao Y.
Title Degradation of EGFR on lung epithelial cells by neutrophil elastase contributes to the aggravation of pneumococcal pneumonia.
Journal J Biol Chem
Abstract Pneumococcus is the main cause of bacterial pneumonia. Pneumococcal infection has been shown to cause elastase, an intracellular host defense factor, to leak from neutrophils. However, when neutrophil elastase (NE) leaks extracellularly, it can degrade host cell surface proteins such as epidermal growth factor receptor (EGFR) and potentially disrupt the alveolar epithelial barrier. In this study, we hypothesized that NE degrades the extracellular domain (ECD) of EGFR in alveolar epithelial cells and inhibits alveolar epithelial repair. Using SDS-PAGE, we showed that NE degraded the recombinant EGFR ECD and its ligand epidermal growth factor, and that the degradation of these proteins was counteracted by NE inhibitors. Furthermore, we confirmed the degradation by NE of EGFR expressed in alveolar epithelial cells in vitro. We showed that intracellular uptake of epidermal growth factor and EGFR signaling was downregulated in alveolar epithelial cells exposed to NE and found that cell proliferation was inhibited in these cells These negative effects of NE on cell proliferation were abolished by NE inhibitors. Finally, we confirmed the degradation of EGFR by NE in vivo. Fragments of EGFR ECD were detected in bronchoalveolar lavage fluid from pneumococcal pneumonia mice, and the percentage of cells positive for a cell proliferation marker Ki67 in lung tissue was reduced. In contrast, administration of an NE inhibitor decreased EGFR fragments in bronchoalveolar lavage fluid and increased the percentage of Ki67-positive cells. These findings suggest that degradation of EGFR by NE could inhibit the repair of alveolar epithelium and cause severe pneumonia.
Volume 299(6)
Pages 104760
Published 2023-6-1
DOI 10.1016/j.jbc.2023.104760
PII S0021-9258(23)01788-X
PMID 37119853
PMC PMC10220274
MeSH Animals Bronchoalveolar Lavage Fluid Epithelial Cells / metabolism ErbB Receptors* / genetics ErbB Receptors* / metabolism Ki-67 Antigen / metabolism Leukocyte Elastase* / metabolism Lung / metabolism Mice Pneumonia, Pneumococcal* / metabolism Proteinase Inhibitory Proteins, Secretory / metabolism
IF 4.238
Human and Animal Cells A549