CD147参与MDSCs免疫表型分类及功能在银屑病发病中的作用及机制研究

Myeloid-derived suppressor cells (MDSCs) is heterogeneous, immature myeloid cells with the ability to suppress the innate and adaptive immune responses. It has identified as novel target cells for immune regulation of psoriasis. However, the upstream regulatory mechanisms of MDSCs in psoriasis have unknown yet. Based on our previous researches, CD147 might be a new therapeutic target for psoriasis. Importantly, we confined that CD147 involved in MDSCs regulation as a potential membrane biomarker. In the current study, we plan to detect the expression of CD147 in MDSCs derived from clinical cases and animal models and assure the effectiveness of CD147. Meanwhile, we also measure the expression of functional molecules (iNOS, Arginase-1, NO, ROS) and secretory proteins (IL-10, TGFβ, sCD147). We will also investigate that MDSCs negative regulate the effector T cells and transform the effector T cells into neutrophil granulocyte. In addition, we will compare with the different types of MDSCs including G-, M-, CD147+, CD147-MDSCs to identify functional differences, and we will explore the potential signaling pathway via CD147 mediation in MDSCs. We want to discover the new signal pathway and target molecule and explain the pathological features of psoriasis including T cell subtype disorder, neutrophil granulocyte abnormal chemotaxis, and excessive keratinocyte proliferation.

MDSCs是骨髓来源的异质性细胞,近年被确定为银屑病新的免疫调控靶点,其免疫表型分子及上游调控尚未完全明确。本课题基于CD147作为银屑病治疗靶点的前期研究基础,发现CD147可作为膜标记分子参与调控MDSCs的数量。本项目拟在临床病例和动物模型中进一步研究CD147在MDSCs的表达情况,明确CD147作为MDSCs表型标记分子的有效性,通过检测功能分子(iNOS,Arginase-1,NO,ROS)和分泌蛋白(IL-10,TGFβ,sCD147)的表达,检测MDSCs对效应T细胞的负调控及其向中性粒细胞转化能力,对比分析G-、M-、CD147+和CD147-MDSC的功能,通过干扰CD147的表达,分析CD147介导MDSCs功能的信号途径。本研究有望探寻出导致银屑病病理三大典型表现(T细胞亚群紊乱、中性粒细胞异常趋化和角质形成细胞过度增殖)的新的通路和靶分子。

MDSCs是骨髓来源的异质性细胞，近年被确定为银屑病新的免疫调控靶点，其免疫表型分子及调控机制尚未完全明确。本研究发现MDSCs，特别是M-MDSCs，在银屑病外周血及皮损中比例增加，与疾病严重程度呈显著正相关。此外，与寻常型银屑病相比，脓疱型银屑病、红皮病型银屑病和关节病型银屑病外周血MDSCs比例显著升高。表皮过表达CD147加重咪喹莫特（IMQ）诱导的银屑病样皮肤炎症，表皮中MDSCs比例显著增加。银屑病患者外周血MDSCs表面CD147表达量显著高于健康对照组。敲降CD147后，MDSCs免疫抑制功能分子（Arg1、iNOS）表达增加，表明银屑病患者外周血MDSCs表面CD147的高表达可能导致MDSCs免疫抑制功能受损。另外，我们使用MDSCs抑制剂（吉西他滨）处理IMQ诱导的银屑病样小鼠模型。结果发现，吉西他滨对MDSCs的抑制缓解了IMQ诱导的银屑病样皮肤炎症，如红斑、皮肤增厚、鳞屑，以及Th17和Treg细胞的浸润。此外，通过RNA-Seq技术，我们验证了MDSCs耗竭的IMQ诱导的银屑病样模型小鼠CD4+T细胞的差异表达基因，如IL-21和Timd2，它们参与Th17细胞分化或T细胞活化。体内中和IL-21R可抑制IMQ诱导的表皮增厚、皮肤MDSCs浸润和脾脏Th17浸润。综上所述，本研究发现异常增加的MDSCs在银屑病发病机制中的重要地位，CD147可能调控MDSCs的免疫抑制功能，靶向MDSCs可能成为银屑病潜在的治疗靶点。