Impact of Nur77 on the initiation and development of E. coli induced acute lung injury

Abstract

Abstract Objectives Orphan nuclear receptor Nur77 (Nur77) has been emerged as a regulator of gene expression in aseptic inflammation, but its role in regulating macrophage response to bacterial infection remains unclear. So, this study was designed to investigate the impact of Nur77 in E. coli induced acute lung injury. Methods Mice with different genotypes (WT, Nur77−/−) were challenged with E. coli intratracheal inoculation. Mortality was assessed hourly. Bronchoalveolar lavage fluid (BALF) and blood were obtained and bacterial burdens were assayed using agar plating method. Lung morphology changes and pulmonary vascular permeability were assessed by HE staining or BALF protein accumulation, separately. The TNF-α level in the BALF were determined by ELISA. Ex vivo, the Nur77 mRNA level expressed on the alveolar macrophages (AMs) under rest or E. coli stimulation were detected by qPCR. The phagocytosis ability of AMs from WT and Nur77−/− mice were further assessed. Results The survival rate of the Nur77−/− mice was 93.3%, while only 31.3% of WT mice survived more than 48 hours. Bacterial counts in the BALF collected from the WT mice were higher than those from the Nur77−/− mice by 10 folds. Along with reduced pulmonary bacterial load, diminished lung injury and permeability were observed in the Nur77−/− group. In addition, we found largely decreased TNF-α level in Nur77−/− mice compared with WT mice in BALF. The mRNA level of Nur77 was largely up-regulated in AMs under E. coli stimulation ex vivo. Functionally, Nur77−/− AMs exhibited increased rates of bacterial engulfment. Conclusions The absence of Nur77 enhances lung immune defense to eliminate invading E. coli and prevents the pathogen from spreading, ultimately improving the outcome.