解毒活血法靶向GATA3信号调控肾脏II型固有淋巴细胞改善狼疮肾炎的新机制

自身抗体介导的肾脏免疫和炎症细胞浸润是狼疮肾炎（LN）自身免疫炎症性肾损伤的重要特征。炎症组织II型固有淋巴细胞（ILC2）募集减少是自身免疫性疾病进展的重要机制。我们发现以狼疮方为代表的解毒活血法能显著改善LN患者热毒血瘀证，抑制狼疮小鼠自身抗体产生及肾组织炎症细胞浸润，并增加ILC2表达，但其作用机制不清楚。我们假设解毒活血法可能通过调节肾脏ILC2功能，形成抗炎微环境，抑制LN自身免疫性炎症反应和肾损伤。本项目拟利用基因敲除、抗体阻断等技术，观察解毒活血法对LN小鼠肾脏ILC2扩增和活化的影响及其在改善肾脏自身免疫炎症性损伤中的作用；探讨这些作用是否通过靶向转录因子GATA3信号调控IL-33/ST2轴而介导；同时研究解毒活血法与糖皮质激素联合应用对ILC2及其信号通路的协同调节作用。该项目旨在揭示解毒活血法治疗LN热毒血瘀证的新机制及其现代科学内涵，有助于中医药学理论的传承与创新。

Renal immune and inflammatory cell infiltration mediated by autoantibodies is an important characteristic of autoimmune inflammatory lesions of the kidney in lupus nephritis (LN). Decreasing recruitment of group 2 innate lymphoid cells (ILC2) in inflammatory tissues is a crucial mechanism for the progression of autoimmune diseases. We found that the Jiedu Huoxue Therapeutic Method, represented by Lupus Recipe, could significantly ameliorate the Noxious Heat and Blood Stasis Syndrome of LN patients, inhibit the production of autoantibodies and the infiltration of inflammatory cells as well as increase the expression of ILC2 in renal tissues of LN mice. But the mechanism remains unclear. We develop a hypothesis that Jiedu Huoxue Therapeutic Method may form an anti-inflammatory microenvironment by modulating the function of ILC2 in the kidney of LN and thereby inhibit the autoimmune inflammatory reaction as well as renal injury. In this study, we are going to determine the effects of Jiedu Huoxue Therapeutic Method on ILC2 expansion and activation as well as its role in the improvement of renal autoimmune inflammatory injury in LN mice with utilization of the technologies such as gene knockout and antibody blocking, etc. We then will investigate whether these effects are mediated by regulating IL-33/ST2 axis via targeting transcription factor GATA3 signaling. Furthermore, we will explore the co-regulation of Jiedu Huoxue Therapeutic Method combined with corticosteroid on ILC2 and its signaling pathway. This study aims to reveal the novel mechanism of Jiedu Huoxue Therapeutic Method on the treatment of LN with the Noxious Heat and Blood Stasis Syndrome and its modern scientific connotation of the treatment, which is conducive to the inheritance and innovation of Traditional Chinese Medicine theory.