IL-17RB+DC亚群促进变应性鼻炎Th2炎症的作用和机制研究

Studies have shown that functional subsets of dendritic cells (DC) fine-tune the nasal mucosal Th2 inflammation of allergic rhinitis (AR); IL-25 has an important role in Th2 inflammation in allergic diseases, but the mechanism is still not clear. We recently reported a significant increase in IL-17RB+ DC subpopulation in peripheral blood of patients with AR, and LPS can induce the expression of this subset of DCs, and IL-25 can enhance its Th2-polarizing function. Therefore, we hypothesize that IL-17RB+ DC subset is a specific DC subpopulation that regulates Th2 inflammation in AR, which is induced by stimulation of TLR signaling, and regulated by IL-25 to promote the downstream Th2 inflammation. The purpose of this study is to investigate the role of IL-17RB+ DC subset in promoting Th2 inflammation and the corresponding intracellular signal transduction in AR, elucidate the signals that induced the generation of IL-17RB+DC subset, and explore the sensitivity of this DC subset to glucocorticoid, by using a combination of in vivo animal and in vitro human studies. This study will be helpful to elucidate the role and mechanism of IL-17RB+ DC subset in the pathogenesis of AR, and provide experimental and theoretical basis for DC-subset-targeting precision treatment.

研究表明功能特异性树突状细胞（DC）亚群精细调控了变应性鼻炎(AR)的鼻黏膜Th2炎症；IL-25在变应性疾病中具有重要促Th2炎症作用，但机制仍不清。我们最近报道了AR患者外周血中IL-17RB+DC亚群显著增多，LPS可诱导该DC亚群的表达，而IL-25可增强其Th2极化功能，据此我们提出科学假设：IL-17RB+DC亚群是AR中调控Th2炎症的特异性DC亚群，其受TLR信号刺激诱导而产生，进而受IL-25调控而促进下游的Th2炎症反应。本研究拟通过人体外实验和AR动物模型，采用DC体外培养、干预和动物体内过继转移的实验策略，深入研究IL-17RB+DC亚群在AR中的促Th2炎症作用和胞内信号转导机制，明晰诱导产生IL-17RB+DC亚群的信号，并探讨该亚群对糖皮质激素的敏感性。本研究将有助于阐明该DC亚群在AR发病中的作用和机制，为靶向该DC亚群的精准治疗提供实验和理论依据。

功能特异性树突状细胞（DC）亚群精细调控了变应性鼻炎(AR)的鼻黏膜Th2炎症，阐明该DC亚群在AR发病中的作用和机制，有望为靶向该DC亚群的精准治疗提供实验和理论依据。我们发现了AR患者外周血中IL-17RB+DC亚群显著增多，并建立人单核细胞来源DC细胞的体外诱导技术和人IL-17RB+DC细胞体外分选技术。我们进一步证实IL-25、IL-17RB+ DC与Th2型炎症的诱导作用三者之间的密切关系。通过CD1c+DC细胞体外培养体系，我们发现IL-25协同IL-33和TSLP对DC的促Th2功能发挥调控效应。此外，通过对TLR配体信号和变应原信号的筛选，我们发现以HDM为代表的变应原信号和TLR信号配体均可促进DC上调表达IL-17RB。以上这些原创性发现先后于2018年和2020年发表于变态反应与免疫学著名杂志Clinical and Translational Allergy（影响因子5.871）和Frontiers in Cell and Developmental Biology（影响因子6.684）。总得来说，这些研究成果为从根本上明晰变应性鼻炎的发病机制提供了理论和实验基础，并为变态性鼻炎靶向IL-17RB+DC的治疗提供了新的突破口。