MSC-exosomes促进巨噬细胞分泌IL-27治疗SS-ILD作用机制

间质性肺疾病(ILD)是干燥综合征(SS)常见并发症,也是SS患者死亡主要原因之一。间充质干细胞来源外泌体(MEX)具有免疫调节作用,避免了细胞移植导致肺栓塞的风险,是治疗新策略。但是MEX治疗SS-ILD作用和机制不明。文献和我们前期研究表明MEX治疗SS鼠ILD有效,肺脏巨噬细胞(Mø)在SS-ILD炎症细胞浸润中起关键作用,以及Mø分泌IL-27具有调节多种淋巴细胞作用。因此,我们提出科学假说:MEX通过调控Mø分泌IL-27来抑制肺部淋巴细胞浸润,治疗SS-ILD。为了验证这一假说,我们应用已构建IL-27基因敲除SS鼠,确认MEX治疗SS-ILD与Mø分泌IL-27的关系;阐明MEX调控Mø分泌IL-27抑制肺部浸润特异淋巴细胞亚群的机制;解析MEX中特异调控Mø分泌IL-27的关键分子。本研究不仅能揭示MEX治疗SS-ILD分子机制,而且为临床转化和推广MEX治疗疾病提供依据。

The interstitial lung disease (ILD) is the common complication of Sjögren’s syndrome (SS) and a leading cause of death among SS patients. Mesencymal stem cell-derived exosomes (MEX) have immunomodulation potential. MEX can reduce potential risks associated with cellular therapies, such as pulmonary embolism. Therefore, MEX may be emerging as a novel clinically-viable therapy. However, the therapeutic effects and underlying mechanisms of MEX on SS-ILD remain unclear. Our previous studies showed that the SS-ILD could be alleviated by infusion of MEX in NOD mice. Many studies have provided evidence for the important role of macrophages (Mø) on lymphocytic infiltration in SS-ILD. Our results also indicated that IL-27 production by Mø regulated many lymphocyte subsets in SS. Therefore, we hypothesized that the beneficial effects of MEX on SS-ILD are related to regulating production of IL-27 by Mø and inhibiting infiltrating lymphocytes in lung. To testify this hypothesis, we aim to explore the effects of MEX on SS-ILD and the role of IL-27 from Mø in inhibiting infiltrating lymphocytes in wild-type and established IL-27 knockout NOD mice. The key molecule within MEX, which regulates IL-27 production by Mø will also be determined. The findings of the present study will reveal the underlying molecular mechanism of beneficial effects of MEX on SS-ILD. The results will also provide evidence for clinical translational research and practical clinical settings.