IL-7介导骨髓多能祖细胞分化在ARDS后免疫力低下中的作用及机制研究

急性呼吸窘迫综合征（ARDS）后免疫力低下与死亡率密切相关。申请人前期发现，持续性炎症导致的ARDS诱发免疫力低下，通过免疫调节有效降低重症病人的死亡率（Cell Host Microbe, 2020），然而ARDS导致免疫力低下的机制尚不清楚。通过ARDS造模，发现骨髓多能祖细胞（MPP）向共同淋系祖细胞分化异常，而免疫细胞分化与代谢密切相关，预实验筛选发现脂肪酸代谢在ARDS中受到抑制。进一步发现ARDS后骨髓微环境发生改变，经转录组测序分析白介素-7可能是调控脂肪酸代谢的重要细胞因子。提示ARDS可能导致骨髓微环境中白介素-7分泌减少，脂肪酸代谢受到抑制，从而MPP分化异常，最终造成免疫力低下。据此本研究围绕MPP分化的内在因素（细胞代谢）和外在因素（骨髓微环境）进行了系统性研究，揭示了代谢和骨髓微环境与免疫的相关性，重点解析ARDS后免疫低下的原因，为ARDS免疫治疗提供新的思路。

Impairment of immunity after acute respiratory distress syndrome (ARDS) is closely associated with mortality. The applicant previously found that ARDS caused by persistent inflammation induces immunodeficiency and effectively reduces the mortality rate of severe patients through immune regulation (Cell Host Microbe, 2020). However, the mechanism of immunodeficiency caused by ARDS remains unclear. After ARDS modeling, it was found that the differentiation of bone marrow multipotent progenitors (MPP) to common lymphoid progenitors (CLP) was abnormal, and the differentiation of immune cells was closely related to metabolism. The preliminary screening showed that fatty acid metabolism was inhibited in ARDS. It was further found that the bone marrow microenvironment was changed after ARDS. Transcriptome sequencing showed that interleukin-7 might be an important cytokine regulating fatty acid metabolism. These results suggest that ARDS may lead to decreased secretion of interleukin-7 and inhibition of fatty acid metabolism in the bone marrow microenvironment, resulting in abnormal differentiation of MPP and ultimately low immunity. In this study, the internal factors (cell metabolism) and external factors (bone marrow microenvironment) of MPP differentiation were systematically studied, revealing the correlation between metabolism and bone marrow microenvironment and immunity, focusing on the analysis of the causes of immunodeficiency after ARDS, and providing a new idea for the immunotherapy of ARDS.