树突状细胞Notch信号在调控哮喘中性粒细胞性炎症中的作用及机制

Neutrophilic inflammation is an important phenotype of chronic airway inflammation of asthma,however,the machinism of neutrophilic inflamation is not well understood.It was found that the bodies' imbalance on Th17/Tregs was related with neutrophilic inflamation.Our previous research shows dendritic cells(DC) plays a key role on regulating the chronic airway inflamation and Th2/Tregs differentiation can be done by Notch signals on DC.This research is focus on how Notch signals on DC effect Th17/Tregs differentiation and the role of Notch signals on DC in airway neutrophilic inflammation. Mouse is Sensitized and challenged through LPS combined with OVA in the model of chronic airway neutrophilic inflammation. The regulated role of DC Notch signals is evaluated by blocking Notch signals on DC and overexpresion of DII4 in DC,as well as using VitaminD3 treated DC in vitro experiment.Also,we investigats the machinism on TH17/Tregs differentiation mediated by Notch signals on DC.To verify this role , neutrophilic inflamation caused by OVA/LPS is evaluated by adoptively transferred with overexpresion of DII4 in DC by using wild and TH17 knockout mouse in neutrophilic inflamation model. This machinism regulated by DC will be a novel issue to clinical therapy and prevention in asthma.

中性粒细胞性炎症是哮喘慢性气道炎症的重要表型之一，但其发生机制不完全清楚。近年发现机体Th17/Tregs比例失衡与中性粒细胞性炎症的发生有关。我们过去的研究证实了树突状细胞(DC)可以通过Notch信号（Jagged）表达来调节Th2/Tregs的极化平衡，从而调控气道炎症反应。本项目提出DC Notch信号(DII4)是调节Th17/Tregs极化平衡的重要机制。本项目将采用LPS联合OVA制备的慢性气道的中性粒细胞炎症模型。在体外实验中,用阻断Notch信号、基因转染DC的高表达Notch配体Dell4以及维生素D3、糖皮质激素等多种因素处理后，观察DC对Th17/Tregs极化的影响;在体内实验中,将高表达Dll4的DC过继给OVA/LPS处理小鼠，研究DC对气道中性粒细胞性炎症的调控作用。本项目通过对DC在调控哮喘气道中性粒细胞性炎症中的作用及机制研究，为临床防治提供新思路。

中性粒细胞性炎症是哮喘慢性气道炎症的重要表型之一，但其发生机制不完全清楚。本实验采用LPS处理典型的哮喘模型动物，诱导成功中性粒细胞性哮喘模型。探讨了中性粒细胞哮喘炎症形成的机制及维生素D3的调节作用。研究结果发现，IL-17A在LPS引发的哮喘中性粒细胞炎症中的起有关键的作用。且IL-17A能抑制哮喘Th2细胞分化，导致气道炎症表型的转换，这一重要发现解释了，临床上见到的中性粒细胞炎症表型哮喘患者，为什么没有典型嗜酸细胞增多的现象。我们在体外实验中证实了VitD3可抑制DC细胞Notch配体DLL4表达而抑制Th17细胞分化。表明树突状细胞（DC）Notch信号在1,25-二羟维生素D3（VitD3）调节Th17细胞分化的起重要作用。本研究结果为临床防治中性粒细胞性哮喘提供了新的思路。