Degradation of EGFR on lung epithelial cells by neutrophil elastase contributes to the aggravation of pneumococcal pneumonia.
Degradation of EGFR on lung epithelial cells by neutrophil elastase contributes to the aggravation of pneumococcal pneumonia.
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中性粒细胞弹性蛋白酶在肺上皮细胞上降解会导致肺炎球菌肺炎的加剧。
DOI：
10.1016/j.jbc.2023.104760
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发表时间：
2023-06
影响因子：
4.8
通讯作者：
Terao, Yutaka
中科院分区：
文献类型：
--
作者：
Isono, Toshihito;Hirayama, Satoru;Domon, Hisanori;Maekawa, Tomoki;Tamura, Hikaru;Hiyoshi, Takumi;Sirisereephap, Kridtapat;Takenaka, Shoji;Noiri, Yuichiro;Terao, Yutaka
肺炎球菌是细菌性肺炎的主要原因。肺炎球菌感染已被证明导致弹性蛋白酶，一种细胞内的宿主防御因子，从中性粒细胞泄漏。然而，当中性粒细胞弹性蛋白酶(NE)在细胞外泄漏时，它可以降解宿主细胞表面蛋白，如表皮生长因子受体(EGFR)，并潜在地破坏肺泡上皮屏障。在本研究中，我们假设去甲肾上腺素能降解肺泡上皮细胞中EGFR的胞外区(ECD)，抑制肺泡上皮修复。SDS-PAGE结果表明，去甲肾上腺素对重组EGFR ECD及其配体表皮生长因子的降解作用被去甲肾上腺素抑制剂拮抗。此外，我们证实了去甲肾上腺素对体外培养的肺泡上皮细胞表达的EGFR的降解作用。我们发现去甲肾上腺素能下调肺泡上皮细胞对表皮生长因子和EGFR信号的摄取，并发现这些细胞的增殖受到抑制，这些对细胞增殖的负面影响可被去甲肾上腺素的抑制剂消除。最后，我们证实了NE在体内对EGFR的降解。肺炎球菌肺炎小鼠支气管肺泡灌洗液中检测到EGFR ECD片段，肺组织细胞增殖标记物Ki67阳性细胞百分率降低。相反，给予NE抑制剂可减少支气管肺泡灌洗液中的EGFR片段，并增加Ki67阳性细胞的百分比。这些结果提示，NE对EGFR的降解可抑制肺泡上皮的修复，导致重症肺炎。
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.