Sirt1调控变应性鼻炎IL-17RB+DC亚群促Th2功能的机制研究

Functional specific dendritic cells(DC) subgroup regulate the Th2 inflammation of allergic rhinitis(AR). Previously, we found that AR patients highly express IL-17RB+ DC subgroup which promote Th2 function, but the mechanism is not clear. Sirt1 is one of the sirtuin protein family which is a kind of type III histone deacetylase. Recent research found that Sirt1 took part in the DC mediated Th2 inflammation in asthma. Our previous research found that IL-25 activate IL-17RB+ DC, then Sirt1 and Interferon Regulatory Factor 4 (IRF4, which is the transform factor that promote Th2 inflammation) were up regulated, but the IRF1 (which promote Th1/17 inflammation) is down regulated. We further silent the RNA of Sirt1, and found that IRF4 and OXL40L (which is the synergetic stimulator that promote Th2 inflammation), but IRF1 up-regulated. Accordingly, we hypothesis that Sirt1 may enhance the IRF4 transcriptional activity through deacetylation of IRF1.to mediate the IL-17RB+ DC promote Th2 inflammation. By using plasmid transfection, RNA silencing, Co-IP, IP, and double luciferase reporter gene technique, we want to answer the key question of how Sirt1 regulate IL-17RB+ DC promote Th2 inflammation. This may show new evidence to further understand the mechanism of IL-17RB+ DC subgroup in the pathogensis of AR, to provides a new target of IL-17RB+ DC subsets for the prevention and control of airway allergic inflammation.

树突状细胞（DC）亚群精细调控了变应性鼻炎(AR)的Th2炎症。我们前期研究发现AR患者高表达具有促Th2极化功能的IL-17RB+DC亚群，但机制仍不清。Sirt1是第Ⅲ类组蛋白去乙酰化酶sirtuin蛋白家族的一员。我们初步研究发现IL-25活化IL-17RB+DC后，其胞内Sirt1和驱动Th2分化的转录因子IRF4表达升高，而驱动Th1/17分化的转录因子IRF1则降低；沉默sirt1基因表达后，IRF4表达显著下降，而IRF1则显著升高。据此我们假设：Sirt1可能通过去乙酰化IRF1而增强IRF4转录活性的机制介导了对IL-17RB+DC促Th2功能的调控。本项目拟采用质粒转染、RNA沉默、Co-IP、IP、双荧光素酶报告基因实验等方法，旨在回答Sirt1如何调控IL-17RB+DC促Th2功能这一关键科学问题，为深入理解DC亚群在气道变应性炎症发病中的作用机制提供新的实验依据

树突状细胞（DC）亚群精细调控了变应性鼻炎(AR)的Th2炎症，AR患者高表达具有促Th2极化功能的IL-17RB+DC亚群，但机制仍不清。我们初步研究发现IL-25活化IL-17RB+DC后，其胞内Sirt1和驱动Th2分化的转录因子IRF4表达升高，而驱动Th1/17分化的转录因子IRF1则降低；沉默sirt1基因表达后，IRF4表达显著下降，而IRF1则显著升高。在本项目支持下，我们发现1）AR患者外周血高表达IL-17RB+DC亚群；2）加入不同的浓度梯度的IL-25，SIRT1表达随时间推移浓度增加；3）沉默sirt1基因的表达后，IRF4和OX40L的表达也显著下降，而IRF1则显著升高。从上述主要结果，我们得出以下结论：Sirt1通过IRF1增强IRF4转录活性的机制介导了对IL-17RB+DC促Th2功能的调控，明确了Sirt1调控IL-17RB+DC促Th2功能的机制。