Sirt5通过促进M2型巨噬细胞分化与功能加重慢性鼻-鼻窦炎的效应与机制研究

Over-activation of Th2 type immune response and increased infiltration of eosinophil are key pathologies of chronic rhinoisnusitis, and also are the characters of refractory CRS. Recent researchs indicate that macrophage activation type (M1/M2) located in various organs or derived from monocytes of blood will directly polarize the activation of adapative immune system (Th1/Th2). We screemed the expression of type III deacytelase family members (Sirt1-7) in monocytes of blood from patients with CRS, and found that the increased expression of Sirt5 was related with increased M2 macrophage infiltration. Sirt5 deficiency decreased the differetiation and function of bone marrow cells upon M2 induction in mouse. We plan to further study the relationship of Sirt5 expression with the progression of CRS; the in vivo and in vitro function of Sirt5 by increasing differentiation and function of M2 macrophages with Sirt5 knockout mice and bone marrow reconsturction system; the mechanism of Sirt5 in promoting differetiation and function of M2 macrophage by signal transduction. We hope that we can provide novel evidence for CRS research and novel targets for drug design.

Th2型免疫过度活化和嗜酸性粒细胞大量浸润是慢性鼻-鼻窦炎(chronic rhinosinusitis, CRS)的重要致病因素，也是难治性CRS的特征。新近研究表明，器官特异性或外周血单核细胞诱导的巨噬细胞的不同分化状态(M1/M2)与免疫系统激活类型(Th1/Th2)紧密相关。申请者前期研究检测了CRS患者外周血单核细胞中Ⅲ型乙酰化酶家族成员(Sirt1-7)表达，发现Sirt5的表达增加与鼻黏膜局部M2型细胞效应分子表达和CRS发病相关；Sirt5缺陷小鼠骨髓细胞诱导M2型巨噬细胞的数量与功能均减弱。申请者拟进一步研究Sirt5的表达异常与CRS的相关性；并应用Sirt5缺陷小鼠和骨髓重建系统研究Sirt5是否可以通过促进M2型分化与功能加重慢性鼻-鼻窦炎的效应；通过信号通路筛选发现Sirt5促进M2巨噬细胞分化与功能的分子机制，为CRS研究提供理论基础及药物研发靶点。

Th2型免疫过度活化和嗜酸性粒细胞大量浸润是慢性鼻-鼻窦炎（CRS）的重要致病因素。新近研究表明，器官特异性或外周血单核细胞诱导的巨噬细胞不同分化状态（M1/M2）与免疫系统激活类型紧密相关。申请者前期研究检测了CRS患者外周血单核细胞中Sirt5的表达，发现Sirt5的表达增加与鼻腔黏膜局部M2型细胞效应分子表达和CRS发病相关。本课题首先从临床出发，通过对临床资料和标本进行收集分析发现，慢性鼻-鼻窦炎（chronic rhinosinusitis, CRS）患者鼻腔黏膜内Sirt5的表达显著增高，且主要表达于M2型巨噬细胞。我们进一步使用卵清蛋白（ovalbumin, OVA）+金黄色葡萄球菌肠毒素B（staphylococcus aureus enterotoxin B, SEB）构建CRS小鼠模型，发现Sirt5在CRS疾病进展过程中可能起着促进M2型巨噬细胞分化、加重Th2炎症反应的作用，并进一步应用Sirt5敲除小鼠证实了这一结果。细胞实验方面，我们分别用WT和Sirt5 -/-小鼠来源的骨髓细胞诱导M2型巨噬细胞，发现Sirt5敲除后M2型巨噬细胞表面分子（CD206）、效应分子（TGF-β、Arg-1）显著减少，证明Sirt5在巨噬细胞分化为M2型过程中起着重要作用；通过转录组测序发现MAPK信号通路可能是其发挥作用的关键信号通路。