Notch1通过糖酵解促进MDSC分化在狼疮中作用机制研究

Previous studies have reported that abnormal changes in myeloid-derived suppressor cells (MDSCs) are associated with lupus disease development. Our previous study showed that the proportion of MDSCs in lupus patients and mice was abnormally elevated. Moreover, the increase in the percentage of MDSCs appeared before systemic pathological symptoms, suggesting that abnormalities of MDSCs may be an initiating factor in the pathogenesis of lupus. Notch1 signaling can regulate MDSC differentiation in a microenvironment-dependent manner, and abnormal activation of Notch1 signaling promotes the onset of lupus. Interestingly, we found that both Notch1 pathway and glycolytic pathway were highly activated in granulocyte-monocyte progenitors (GMPs) of lupus mice. The inhibition of the Nocth1 pathway significantly decreased the number of MDSCs and down-regulated the rate of glycolysis in GMPs. Therefore, we hypothesize that the highly activated Notch1 pathway promotes GMPs differentiate into MDSCs by up-regulating glycolysis and thus aggravates the development of lupus. In this study, we intend to examine the critical role of Notch1 in regulating the differentiation of GMPs to MDSCs and evaluates the effect of targeting Notch1 pathway in the treatment of lupus. These findings will give us new insights into the pathogenesis and treatment of lupus.

研究报道狼疮与髓系抑制性细胞（MDSC）的异常变化相关。我们前期研究发现，狼疮患者及模型小鼠体内MDSC比例异常升高，且MDSC升高出现在系统性病理症状之前，提示MDSC增多可能是导致狼疮发生的始动因素。Notch1信号以微环境依赖的方式调控MDSC的分化，且Notch1信号的异常活化促进狼疮发病。我们前期还发现，狼疮小鼠的骨髓粒-单核系祖细胞（GMP）中Notch1通路高度活化，糖酵解水平显著升高；抑制Nocth1通路可显著下调GMP细胞的糖酵解速率，降低MDSC数量。我们提出科学假说，高度活化的Notch1通路通过上调糖酵解促进GMP向MDSC分化，加剧狼疮的发展。本项目拟在前期研究工作基础上，明确Notch1通过调节糖酵解反应调控GMP向MDSC的分化过程，进一步探索Notch1调控糖酵解的分子机制；评价靶向Notch1通路治疗狼疮的效果；可望为狼疮发病机制及治疗提供新的思路。

我们的研究证实Notch1信号通路在SLE的发展过程中发挥着至关重要的作用，抑制Notch1信号通路能够显著缓解狼疮小鼠疾病症状，显著减少MDSC前体细胞GMP的数目，也能够在体内和体外抑制MDSC的扩增，提示Notch1可能通过促进GMP向MDSC分化加剧狼疮发病。本研究为揭示MDSC在狼疮中异常扩增的机制提供了新的机制，也为SLE的治疗提供了一个新的靶标。这部分的研究结果以题为“Notch1 signalling controls the differentiation and function of myeloid-derived suppressor cells in systemic lupus erythematosus”发表在Immunology 期刊上（IF=7.2，项目负责人为第一作者）。此外，我们对MDSC在感染中的作用进行了探索，这部分研究成果以题为“Umbilical cord mesenchymal stem cells enhance the therapeutic effect of imipenem by regulating myeloid derived suppressor cells in septic mice”发表在Annals of Translational Medicine期刊上（IF=3.6，项目负责人为共第一作者）。