骨髓来源抑制性细胞通过NF-κB信号途径对非酒精性脂肪性肝炎中T细胞的免疫调节作用

The incidence rate of non-alcoholic fatty liver disease (NAFLD) is increasing. Simple steatosis in the early stage may gradually develop into fatty hepatitis(NASH), then towards hepatic fibrosis and liver cirrhosis, even hepatic cancer. Hepatic inflammation plays a critical role in NASH, but the mechanism is unknown. Myeloid derived suppressor cell (MDSC) is a heterogenous population containing myeloid progenitor and immature myeloid cells, in our previous study, we found a significant increase in the numbers of hepatic/peripheral MDSCs in NAFLD patients and murine model. MDSCs could inhibit CD4+T cells proliferation when co-cultured with T cells. We thought that by NF-κB pathway MDSCs would regulate T cells immune in NASH. We found that reinfusion of hepatic MDSCs could not only block NF-κB signal pathway and IL-6 expression, but also inhibit functions of T cells and promote Treg cells proliferation, preventing the activation of hepatic stellate cells in NASH. We believe that MDSCs have protective effects on suppressing inflammation in NASH. In this study, we will investigate the immunomodulatory effects of MDSCs on T cells immune mediated by NF-κB signal pathway in NASH. we will apply flow cytometry, western-Blot, real-time PCR to assess levels of NF-κB, IL-6, and observe activation of HSC. It may provide new targets for the prevention and treatment of NASH.

非酒精性脂肪性肝病发病率俱增，可进展至非酒精性脂肪性肝炎(NASH)、肝纤维化和肝硬化，甚至肝癌。肝内炎症反应是NASH的重要病理学基础，仍机制不明。前期研究发现，髓系抑制性细胞(MDSC)作为骨髓来源的未成熟细胞，在非酒精性脂肪肝患者和小鼠模型外周血和肝脏中数量增高；与T细胞共同培养时，抑制CD4+T细胞增殖。我们假设，MDSC通过NF-κB通路在NASH中对T细胞进行免疫调节。过继回输肝脏MDSC可抑制NF-κB表达，降低IL-6表达，抑制肝内T细胞效应，改变调节性T细胞数量，阻止肝星状细胞活化。我们认为MDSC在NASH中具有抑炎的保护作用。本研究拟阐述在NASH进展过程中MDSC介导的T细胞免疫反应及机制，用流式细胞技术、Western-Blot、Real-timePCR等方法观察小鼠肝内NF-κB通路和IL-6的改变，观察HSC活化指标，为治疗NASH的防治提供新思路。

随着过国内生活水平的不断提高，目前非酒精性脂肪性肝病已经成为我国第一大肝病，将来必将成为影响人们健康的重要疾病。骨髓来源的免疫抑制细胞（MDSCs）是一种新发现的免疫抑制细胞，在肿瘤、炎症等多种疾病的发病过程中有重要的作用。我们的研究发现MDSCs细胞在MCD诱导的非酒精性脂肪性肝病中发挥这重要的作用，其中对肝细胞脂肪变性及肝内炎症浸润过程均有着作用；而不同类型来源的MDSCs细胞发挥的生物学功能不尽相同，其中单核型的MDSCs（Ly6G-MDSCs）能够明显缓解肝细胞脂肪变性，并能减轻肝内炎症反应；而多核型的MDSCs（Ly6G+MDSCs）反而促进的肝细胞脂肪变性，加重肝内炎症反应。进一步的体外实验发现PI3Kγ可能在MDSCs细胞的分化过程总发挥重要的作用。为我们将来在非酒精性脂肪性肝病的免疫学治疗提供依据，我们的研究解结果提示单核细胞来源的MDSCs细胞在将来有望能够在NASH的免疫治疗、甚至肝细胞脂肪变放面发挥重要的作用，而粒细胞来源的MDSCs细胞不适合于NAFLD的治疗研发。进一步的研究PI3Kγ在MDSCs中的功能，将能进一步阐述MDSCs的分化、增殖的特性，有望发现新的调控MDSCs生物学功能的靶点。