NR4A1 Promotes LPS-Induced Acute Lung Injury through Inhibition of Opa1-Mediated Mitochondrial Fusion and Activation of PGAM5-Related Necroptosis

Abstract

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.