Department of Respiratory Medicine, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China.
Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, China.
Oxid Med Cell Longev. 2022 Feb 18;2022:6638244. doi: 10.1155/2022/6638244. eCollection 2022.
Mitochondrial dysfunction and necroptosis have been perceived as the primary molecular mechanisms underscoring acute lung injury. Meanwhile, nuclear receptor subfamily 4 group A member 1 (NR4A1) is considered a regulator of inflammation-related endothelial injury in lung tissue although the downstream molecular events remain elusive. In this study, we employed NR4A1 mice to decipher the role of NR4A1 in the onset and progression of acute lung injury with a focus on mitochondrial damage and necroptosis. Our results demonstrated that NR4A1 was significantly upregulated in lipopolysaccharide- (LPS-) treated lung tissues. Knockout of NR4A1 overtly improved lung tissue morphology, inhibited inflammation, and reduced oxidative stress in LPS-treated lung tissue. A cell signaling study suggested that NR4A1 deletion repressed levels of PGAM5 and attenuated LPS-mediated necroptosis in primary murine alveolar epithelial type II (ATII) cells, the effects of which were mitigated by PGAM5 overexpression. Moreover, LPS-mediated mitochondrial injury including mitochondrial membrane potential collapse and mitochondrial oxidative stress was drastically improved by NR4A1 deletion. Furthermore, NR4A1 deletion preserved mitochondrial homeostasis through activation of Opa1-related mitochondrial fusion. Silencing of Opa1 triggered mitochondrial dysfunction in NR4A1-deleted ATII cells. Taken together, our data identified NR4A1 as a novel regulator of LPS-related acute lung injury through regulation of mitochondrial fusion and necroptosis, indicating therapeutic promises of targeting NR4A1 in the treatment of acute lung injury in clinical practice.
线粒体功能障碍和坏死性凋亡已被认为是急性肺损伤的主要分子机制。同时，核受体亚家族 4 组 A 成员 1（NR4A1）被认为是肺组织中炎症相关内皮损伤的调节剂，尽管下游分子事件尚不清楚。在这项研究中，我们使用 NR4A1 小鼠来阐明 NR4A1 在急性肺损伤发病和进展中的作用，重点关注线粒体损伤和坏死性凋亡。我们的结果表明，NR4A1 在脂多糖（LPS）处理的肺组织中明显上调。NR4A1 的缺失明显改善了 LPS 处理的肺组织的形态，抑制了炎症，并减少了氧化应激。细胞信号研究表明，NR4A1 的缺失降低了 PGAM5 的水平，并减弱了 LPS 介导的原代小鼠肺泡上皮细胞 II 型（ATII）细胞中的坏死性凋亡，而过表达 PGAM5 则减轻了这种作用。此外，LPS 介导的线粒体损伤，包括线粒体膜电位崩溃和线粒体氧化应激，在 NR4A1 缺失后得到明显改善。此外，NR4A1 的缺失通过激活 Opa1 相关的线粒体融合来维持线粒体的动态平衡。沉默 Opa1 触发了 NR4A1 缺失的 ATII 细胞中的线粒体功能障碍。总之，我们的数据表明，NR4A1 通过调节线粒体融合和坏死性凋亡，成为 LPS 相关急性肺损伤的一个新的调节因子，表明在临床实践中靶向 NR4A1 治疗急性肺损伤具有治疗潜力。
