肺巨噬细胞表达NR4A1核受体在脓毒症致急性肺损伤中的作用及机制研究

Pulmonary macrophage as a major type of innate immune cell resides in the lung tissue, which mediates the initiation and development of ALI/ARDS. M1/M2 macrophage polarization is the very important regulatory response in this process. NR4A1 is expressed on macrophage, functions as an early-phase induced gene, participates in the regulation of gene expression profile of macrophage, M1/M2 macrophage polarization and inflammatory response. Our preliminary studies have shown that NR4A1 was expressed on pulmonary macrophage. LPS stimulated isolated-alveolar macrophage, NR4A1 levels was upregulated, achieved the peak time point at 1h. In vivo experiments, it also demonstrated that NR4A1 expression of pulmonary macrophage enhanced in sepsis induced ALI mice. Therefore, we hypothesize that NR4A1 will be involved in the pathogenesis of sepsis induced ALI via modulating M1/M2 macrophage polarization and inflammatory response. The present project will apply kinds of molecular biological skills (eg. siRNA, target gene knock-out, et al.), investigate the interrelation among NR4A1 levels of pulmonary macrophage, lung injury, pulmonary leukocytes infitrarion and inflammation induced by sepsis, to clarify the roles and mechanism of NR4A1 in ALI, and further to explore molecular mechanism how NR4A1 controls the M1/M2 macrophage polarization and inflammation. Ultimately, our project would provide new ideas and targets in the prevention and management of ALI.

肺巨噬细胞是定居于肺组织的一类主要的固有免疫细胞，参与ALI/ARDS的启动和发展。M1/M2型巨噬细胞极化是其参与调节ALI/ARDS发生发展的关键环节。NR4A1核受体表达于巨噬细胞，作为早期反应基因，参与调节巨噬细胞基因表达谱、M1/M2型巨噬细胞极化和炎症反应。我们前期实验证实NR4A1表达于肺巨噬细胞；LPS刺激后，NR4A1表达升高，1h达峰；ALI小鼠肺泡巨噬细胞NR4A1表达增高。因此，我们推测：NR4A1核受体通过调控M1/M2型肺巨噬细胞极化，调节炎症反应，参与脓毒症致ALI的发生发展。本项目拟从整体、细胞、分子水平，分析NR4A1与脓毒症致ALI发生、发展的相关性；明确NR4A1在脓毒症致ALI中的作用及机制；深入探讨NR4A1调控M1/M2型肺巨噬细胞极化的分子机制。最终，阐明NR4A1在脓毒症致ALI发生、发展中的作用及分子机制，为ALI防治提供新思路、新靶向。

肺巨噬细胞是定居于肺组织的一类主要的固有免疫细胞，NR4A1核受体表达于巨噬细胞，作为早期反应基因，参与调节巨噬细胞免疫炎症调节作用。本项目围绕“肺巨噬细胞表达NR4A1核受体在脓毒症致急性肺损伤中的作用和机制”，首次证实了在E.coli诱导急性肺损伤小鼠中，NR4A1基因敲除（NR4A1 KO）显著减轻肺损伤程度，提高小鼠生存率；揭示了NR4A1基因表达于多种固有免疫细胞（包括：pDCs、BMDMs和AM），并且提示NR4A1可能是调节Imiquimod诱导pDC细胞表达IFN-β和IL-6基因的调控因子；明确了肺泡巨噬细胞表达NR4A1核受体不影响巨噬细胞M2型分化；阐明了NR4A1核受体通过调节RAC1活性，从而介导对巨噬细胞吞噬/杀菌功能的调控，参与脓毒症致急性肺损伤的分子机制。研究工作为进一步深入解析调控巨噬细胞免疫炎症功能分子机制提供了新方向，并且NR4A1核受体有望成为今后研发脓毒症致急性肺损伤特异性靶向治疗药物的新靶点，为今后开展临床转化和应用研究提供了理论基础。