c-Rel调控Th17细胞分化的分子机制研究

Recently, a newly defined population of IL-17-producing CD4+Th cells, named Th17 cells, has been identified and shown to be involved in the models of inflammatory and autoimmune diseases. The Th17 cells utilize the retinoid-related orphan receptor-γ (Rorg) to specify their differentiation and lineage-specific function. The identification of RORγT as a lineage-specific factor of Th17 cells represents a major breakthrough in the research of Th17 cells. However, how Rorg gene is switched on during Th17 differentiation is largely unclear. We recently discovered that c-Rel drived Th17 differentiation by binding to and activating two distinct Rorg promoters, which control RORγT and RORγ mRNA expression respectively. Therefore, we hypothesize that c-Rel serves as a primary transcription factor in the Th17 differentiation program. To test this hypothesis, by using a combination of genetic, biochemical, and genomic techniques, we will determine whether and how c-Rel initiates 1) the chromatin remodeling of the pioneer Rorg element and 2) the enhanceosome formation at the Rorg promoters during Th17 cell differentiation. Then we will find out if c-Rel can become a therapeutic target for inflammatory and autoimmune diseases. Our study will not only promote an in-depth understanding of the biological function of Th17 cells and c-Rel, but also contribute to the development of novel c-Rel blocking drugs for the treatment of inflammatory diseases.

近年来，新定义了一种能产生IL-17的CD4+Th细胞群体，命名为Th17细胞，它们在多种炎症和自身免疫性疾病模型中被识别并发挥作用。Th17细胞利用维甲酸相关孤儿核受体γ（Rorg）来实现分化的特异性和具有细胞系特有的功能。识别RORγT作为一种Th17细胞特异的因子是Th17细胞研究中的一个重大突破。但是，在Th17细胞分化过程中如何启动Rorg基因尚不清楚。我们最近的研究发现，c-Rel通过连接并活化2个不同的分别控制RORγT和RORγ mRNA表达的Rorg启动子，从而驱动Th17细胞的分化。因此，我们提出c-Rel是Th17细胞分化过程中的初始转录因子这一假说。为了验证这一假说，我们将采用遗传、生化和基因组学等技术相结合的方法，来研究c-Rel对启动Rorg元件的染色质重塑和在Th17细胞分化过程中在Rorg启动子处形成增强体这两个过程的调控机制，从而确定c-Rel能否成为炎症和自身免疫性疾病的治疗靶点。我们的研究不仅能够促进对Th17细胞及c-Rel生物学作用的深入理解，而且也有助于开发治疗各种炎症性疾病的c-Rel阻断性创新药物。

在多发性硬化症的发病过程中，Th1和Th17细胞发挥了关键性的中枢神经系统致病性作用。巨噬细胞被报道在Th1和Th17细胞的分化中发挥了重要作用，但能否通过调节巨噬细胞特定基因的水平来调控巨噬细胞、从而抑制致病性的Th1和Th17应答，目前研究不多。而在本项目的研究中，我们通过纳米材料递送靶向c-Rel的siRNA，成功地敲低了EAE小鼠CNS浸润的巨噬细胞中的c-Rel，然后我们发现巨噬细胞中的NFKb靶基因中一些促炎细胞因子基因表达水平显著下降，比如IL-1beta和IL-12的p40等。同时，我们发现小鼠的EAE发病严重程度显著下降，CNS浸润的淋巴细胞明显减少，而MOG特异性的Th1和Th17应答也明显减弱，体现在血清IFNgamma和IL-17A水平的下降、脾脏MOG特异性细胞的减少和CNS浸润的Th1和Th17水平的减少等等。总而言之，我们的研究结果发现靶向巨噬细胞的c-Rel能削弱CNS致病性Th1和Th17应答的水平，提示巨噬细胞的c-Rel可能是潜在的多发性硬化症的治疗靶点。