细菌DNA经Sgk1/Nedd4L信号通路诱导肥大细胞活化参与慢性自发性荨麻疹发病的机制研究

Elucidating the pathogenesis of refractory chronic spontaneous urticaria (RCSU) is critical for improving the clinical management of urticaria. Recent years, foreign and our series of studies have uncovered the basic nature of complicated immuno-inflammation induced by inflammatory stimuli and/or specific IgE mediated activation of skin mast cells (MC). Furthermore, our recent research work showed that bacterial DNA from intestinal bacterial translocation was extremely likely to be the key factors in maintaining the systemic inflammatory response in patient with RCSU, and the signal pathway of serum and glucocorticoid inducible protein kinase1(Sgk1)/neural precursor cell-expressed developmentally down-regulated gene 4-like(Nedd4L), involved in IgE-mediated activation of skin MC, might has important regulatory effects on intestinal bacterial DNA-mediated skin MC activation and expression pattern of inflammatory mediators. Current project intends to firstly analyze the association between intestinal bacterial translocation and inflammatory mediator expressions in patients with RCSU, and then explore the possible roles of Sgk1/Nedd4L signaling pathway in regulating intestinal bacterial DNA -induced activation of skin MC and the release of inflammatory mediators at the cellular and molecular levels. The clarification on the role of Sgk1/Nedd4L signaling molecules in inflammatory stimuli and/or specific IgE-mediated activation of skin MC will provide new evidence to elucidate the cause and mechanism of complicated inflammation in RCSU, and will lay theoretical basis for improving the clinical treatment of RCSU with new bio-targeted therapy.

阐明难治性慢性自发性荨麻疹（RCSU）的发病机制是提升荨麻疹临床处置水平的关键。新近国外及我们前期的研究均提示，RCSU病理生理基础是由炎性刺激物和/或特异性IgE共同激活皮肤肥大细胞（MC）导致更加复杂的免疫炎症形成；我们近期研究工作还表明，肠道细菌移位至外周血释放的细菌DNA很可能是维持RCSU系统性炎症反应的关键因素，且参与IgE激活皮肤MC的血清和糖皮质激素诱导蛋白激酶1（Sgk1）/神经前体细胞表达发育调控样基因4L（Nedd4L）信号通路可能对肠源性细菌DNA介导皮肤MC活化及炎症介质表达模式有重要调控作用。本项目拟在分析RCSU患者肠道细菌移位与机体炎症介质表达模式关联性基础上，从细胞和分子水平探讨Sgk1/Nedd4L信号通路调控肠源性细菌DNA诱发皮肤MC活化释放炎症介质的机制，为阐明RCSU复杂炎症形成的原因及机制提供全新的研究证据，为寻找新的生物靶向疗法提供理论基础。

阐明抗组胺抵抗的难治性慢性自发性荨麻疹（RCSU）的发病机制是提升荨麻疹临床处置水平的关键。新近国外及我们前期的研究均提示，RCSU病理生理基础是由炎性刺激物和/或特异性IgE共同激活肥大细胞导致更加复杂的免疫炎症形成。本项目首先基于人群粪便及血清标本的检测发现，RCSU患者肠粘膜通透性增加且肠道细菌移位明显，其粪便细菌Prevotella、 Megamonas 和Escherichia显著增加 ， 而Blautia、Alistipes、 Anaerostipes和Lachnospira却显著减少，并发现粪便Escherichia丰度与系统炎症反应显著正相关。进一步采用源于Escherichia的细菌DNA（btDNA）体外刺激肥大细胞（LAD2细胞）的研究发现：1）btDNA不能直接诱导LAD2细胞脱颗粒，但可促进其表达炎症介质（IL-6和TNF-α），该作用与btDNA中非甲基化CpG与细胞TLR9表达有关；2）敲减脾酪氨酸激酶（Syk）表达或抑制Syk磷酸化可抑制btDNA的促炎特性；3）神经前体细胞表达发育调控样基因4L （Nedd4L）与磷酸化Syk互作而抑制btDNA/Syk/炎症通路，但btDNA亦激活血清和糖皮质激素诱导的激酶1（Sgk1）而磷酸化Nedd4L；4）敲减Sgk1表达或抑制Sgk1磷酸化通过维持Nedd4L的泛素连接酶活性而抑制btDNA的促炎特性；5）btDNA预处理可通过增强Sgk1与Nedd4L磷酸化而促进IgE介导LAD2细胞脱颗粒。综上结果，本项目得出如下结论：肠道菌群失衡及肠道细菌移位参与了RCSU的形成，移位入血的细菌DNA可通过TLR9/Syk通路促进肥大细胞产生炎症介质，该特性与细菌DNA激活Sgk1抑制Nedd4L泛素连接酶活性有关。本项目为阐明RCSU复杂炎症形成的原因及机制提供了全新的研究证据，为寻找新的生物靶向疗法提供了理论基础。

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