银屑病中LRG通过TGF-β信号通路调控IL17+Foxp3+CD4+T细胞向Th17细胞极化的作用及机制研究

Psoriasis is a common inflammatory skin disease, and there exist high-expressed Th17 cells and the imbalance between Foxp3+ Treg cells and Th17 cells, which are the important factors of the pathogenesis. Previous studies have demonstrated that during the process of Foxp3+ Treg cells differentiated into Th17 cells, there existing IL-17+Foxp3+CD4+T cells which also are detected in psoriasis. Our preliminary experiment also shows the expression of IL-17+Foxp3+CD4+T cells in psoriatic lesions, however, the mechanism of which polarization into Th17 cells remains undefined.. Leucine-rich alpha 2 glycoprotein is an approximately 50-kDa glycoprotein that contains repetitive sequences with a leucine-rich motif. Our previous studies showed the levels of LRG in serum of psoriasis were significantly higher than that in normal. Also the expression of LRG in peripheral blood and lesions of mouse with psoriasis increased when compared with control, and LRG silencing relieved the symptom of psoriasis. As reported, LRG promoted Th17 differentiation by the enhancement of TGF-β pathway and in arthritis development. Based on these findings, we proposed that LRG promotes IL-17+Foxp3+CD4+T cells polarized into Th17 cells partly through enhancement of TGF-β pathway in psoriasis. So the present study is to investigate the new mechanism of psoriasis and to provide a potential therapy strategy.

银屑病是一种常见的慢性炎症性皮肤病，Th17细胞高表达和Foxp3+Treg/Th17细胞比例失衡是发病机制中的重要环节。研究发现Foxp3+Treg细胞可向Th17细胞转化，其间可存在IL-17+Foxp3+CD4+T细胞。我们已发现银屑病皮损处表达IL-17+Foxp3+CD4+T细胞，与文献报道一致，但其向Th17细胞极化的机制不明。分子量为50kDa的富亮氨酸α2糖蛋白（Leucine-rich alpha 2 glycoprotein，LRG），已被证实在关节炎模型小鼠中通过TGF-β信号通路促进Th17细胞极化。我们发现银屑病患者和模型小鼠血清中LRG显著高表达，Lrg-siRNA干扰后可明显缓解其进展，因此推测：银屑病中LRG也可能通过TGF-β信号通路诱导IL-17+Foxp3+CD4+T细胞向Th17细胞极化，发挥致炎效应，从而揭示银屑病新的发病机制，为治疗提供潜在靶点。

Th17细胞在银屑病的发病机制中起关键作用，其信号通路尚不明确。本研究旨在通过体外和体内试验，证实LRG通过结合TGF-β受体激活下游Smad信号通路，诱导IL-17+Foxp3+CD4+T细胞极化成Th17细胞，增强炎症反应，从而阐明完善银屑病免疫调节机制。实验结果：.①明确了LRG在银屑病患者外周血中与IL-17+Foxp3+CD4+T细胞及Th17细胞之间的关联，且和银屑病PASI评分存在一定相关性：PASI评分越高，关联性越强；反之，较弱。应用前景：IL-17+Foxp3+CD4+T细胞及Th17细胞的含量间接反映银屑病炎症程度，可服务于临床。.②通过体外实验诱导IL-17+Foxp3+CD4+T细胞，应用流式、ELISA、Western-blot等实验手段，阐明LRG通过结合TGF-β受体，激活下游Smad2等信号分子，最终促进IL-17+Foxp3+CD4+T细胞向Th17细胞方向的极化。科学意义：完善了银屑病IL-17信号通路家族。.③已完成动物部分前期干预实验，结果显示：LRG干扰及TGF-β受体拮抗剂的干预，可部分扭转银屑病的炎症程度，验证了LRG在银屑病发病机制中的作用，后续HE病理、免疫组化、ELISA和Western-blot等实验正在进行，将进一步验证LRG通过TGF-β信号通路促进IL-17+Foxp3+CD4+T细胞向Th17细胞转化的机制。应用前景：LRG干扰可成为潜在治疗药物候选，以服务于临床。.④ 通过体内和体外实验阐明Sortilin通过PI3K-AKT信号通路调节角质细胞增殖和凋亡的研究（已发表SCI收录文章）：通过体内和体外实验，阐明银屑病新的发病机制，Sortilin可为银屑病提供潜在治疗靶点。