IL-17RB+记忆性Th2细胞调控形成高表达IL-25内型鼻息肉Th2炎症的作用和机制研究

鼻息肉(NP)呈高度异质性，针对疾病内型进行精准治疗是未来方向。新近我们报道了具有更重Th2炎症表型的IL-25高表达NP内型。为探索IL-25诱导Th2炎症的关键效应细胞，我们预实验发现NP来源IL-17RB+(IL-25受体)记忆性Th2细胞(mTh2)在IL-25诱导下高表达Th2因子，且可被IL-25中和抗体抑制。那么，IL-25如何激活IL-17RB+mTh2胞内信号转导？文献和我们预实验提示：IL-25可激活STAT5-GATA3通路，上调Th2因子转录。据此我们提出：IL-25以IL-17RB+mTh2为靶细胞，激活其STAT5-GATA3通路，促进NP中Th2炎症。本项目拟进一步：明确IL-17RB+mTh2在IL-25内型NP的Th2炎症中的调控作用；研究IL-17RB+mTh2的胞内信号转导机制；探索以IL-17RB+mTh2为靶点的IL-25内型NP精准治疗的可行性。

Nasal polyps (NP) are highly heterogeneous, and precise treatment based on their endotypes is imperative. Recently, we reported that a nasal polyp (NP) endotype which highly expressed IL-25 has more severe features of Th2 inflammation. In order to explore the key effector cells of IL-25-induced Th2 inflammation, we found that memory Th2 cell (mTh2) which expressed IL-17RB (IL-25 receptor) overexpressed Th2 inflammatory cytokines induced by IL-25 and the expression could be inhibited by IL-25 neutralizing antibody. So, how does IL-25 activate intracellular signal transduction of IL-17RB+ mTh2? Referring to the latest literature, we found that IL-25 can activate STAT5-GATA3 pathway and up-regulate Th2 factor transcription on the basis of previous studies. Therefore, we hypothesize that IL-25 may induce Th2 inflammation in NP by activating IL-17RB +mTh2 by its STAT5 pathway, thus forming the immunopathological features of the NP endotype. In this study, we intend to further clarify the regulatory role of IL17RB+ mTh2 in Th2 inflammation of the NP endotype which highly expressed IL-25, study the molecular mechanism of intracellular signal transduction in IL-17RB+mTh2, and explore the feasibility of precise treatment of this NP endotype targeting IL-17RB+ mTh2.