Ceramide-1-Phosphate: a new player in modulating DC in allergic airway inflammation!?

树突状细胞在诱导和维持辅助性T细胞（TH2）对哮喘患者吸入过敏原的反应中起重要作用。最近的研究表明鞘脂介质（如神经酰胺、神经酰胺-1-磷酸（C1P）和鞘鞘醇-1-磷酸（S1P））通过细胞内信号通路和/或与特异性质膜受体结合参与调节炎症。虽然S1P在哮喘发病机制和DC生物学中的作用已被广泛研究，但对C1P知之甚少。本课组初步发现C1P可能通过调节DC功能对急性变应性气道炎症起抗炎作用。在本研究中，我们想探讨C1P是否能抑制急性和慢性实验性哮喘的所有主要特征；2)体外和体内C1P调节骨髓源DC的成熟、细胞因子产生和T细胞启动能力3)体内C1P影响内源性DC的迁移和th2启动；4) C1P影响人单核细胞源性dc功能的成熟、细胞因子产生和T细胞启动。5) C1P是否与ormdl表达相互作用？6)最后，C1P是否能够抑制一般和dc驱动的人源scid哮喘小鼠模型的变应性气道炎症。本项目将阐明C1P在哮喘dc -功能中的作用。

Dendritic cells have been shown to be essential in the induction and maintenance of T helper 2 (TH2)-cell responses to inhaled allergens in asthma. Recent studies suggest that sphingolipid mediators (like ceramide, ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P)) are involved in regulating inflammation, via intracellular signalling pathway and/or binding to specific plasma-membrane receptors. While the role of S1P in the pathogenesis of asthma and DC biology has been extensively studied, little is know about C1P. Preliminary data by our group revealed that C1P might exert anti-inflammatory effects in acute allergic airway inflammation via modulation DC function. In the present study we want to investigate whether: 1) C1P can inhibit all cardinal features of acute and chronic experimental asthma; 2) C1P modulates the maturation, cytokine production and T cell priming capacity of bone marrow derived DC in vitro and in vivo 3) C1P effects the migration and TH2-priming of endogenous DC in vivo; 4) C1P influences maturation, cytokine production and T cell priming of human monocyte derived DC-function. 5) Does C1P interact with ORMDL-expression? 6) Finally, is C1P able to inhibit allergic airway inflammation in general and DC-driven humanized SCID-mouse model of asthma. This project will elucidate the role of C1P on DC-function in asthma.