Mast Cell S1P Receptor2 in the initiation and progression of chronic inflammation

描述(申请人提供)：慢性炎症通常是治疗失败和耐药的结果。肥大细胞位于血管周围，通过免疫球蛋白E(Fc？RI)高亲和力受体(Fc？RI)的变应原交联，释放预先形成的和从头合成的各种炎症介质，包括组胺、细胞因子和趋化因子，是炎症反应的主要反应细胞。此外，被激活的肥大细胞可以释放鞘氨醇代谢产物鞘氨醇-1-磷酸(S1P)，它是在鞘氨醇激酶(SphK)激活时产生的。分泌的S1P可以与自己的受体结合，如肥大细胞上表达的2型受体(S1P2)。一些慢性炎症性疾病的小鼠模型已经建立了炎症灶中肥大细胞数量的早期增加，这表明他们在这一过程中进行了早期干预。我们已经证明，肥大细胞S1P2在与急性过敏性炎症相关的早期事件中是必不可少的，其中包括肺血管周围的浮肿。水肿会促进随后炎症细胞的募集，血管数量的增加也有利于炎症细胞的募集，这是慢性炎症中常见的特征。我们建议使用肥大细胞介导的肺部炎症的小鼠模型来研究肥大细胞表达的S1P2在疾病进展中的作用，并确定它如何导致持续性炎症。利用药理学、分子和遗传学的方法，我们发现了一条连接S1P2和STAT3转录因子的新的信号通路，以及破坏这一途径可能如何潜在地消除慢性炎症中观察到的重塑。本应用的目的是：确定S1P2在起始炎性细胞浸润和传播炎症中的作用，阐明新发现的信号通路及其与重塑的相关性，建立以肥大细胞/S1P/S1P2轴为靶点的体内模型，试图阻止与慢性炎症性疾病相关的特征。由于针对单个介质的靶向未能预防持续性炎症，我们预计我们提出的研究将有助于更好地了解其潜在机制，并为更多针对炎症局部调控途径的机械化治疗铺平道路，肥大细胞表达的S1P2起核心作用。

DESCRIPTION (provided by applicant): Chronic inflammation is often the result of treatment failure and drug resistance. Located around blood vessels, mast cells are primary responders in inflammation by releasing pre-formed as well as de novo synthesized various inflammatory mediators, including histamine, cytokines, and chemokines upon allergen cross-linking of high affinity receptors for IgE (Fc?RI). In addition, activated mast cells can release the sphingolipid metabolite sphingosine-1-phosphate (S1P), generated upon sphingosine kinase (SphK) activation. Secreted S1P can bind to its own receptors, such as the type 2 receptor (S1P2) expressed on mast cells. Several mouse models of chronic inflammatory disorders have established an early increase in mast cell number in inflammatory foci, suggesting their early intervention in the process. We have shown that mast cell S1P2 is essential to the early events associated with acute signs of allergic inflammation, among which edema surrounding the blood vessels in the lungs. Edema promotes subsequent recruitment of inflammatory cells, also favored by increased number of blood vessels, features commonly observed in chronic inflammation. We are proposing to study the contribution of mast cell-expressed S1P2 in the disease progression using mouse models of mast cell-mediated pulmonary inflammation and define how it could lead to persistent inflammation. Using pharmacological, molecular and genetic approaches, we have discovered a new signaling pathway linking S1P2 to Stat3 transcription factor and how disrupting this pathway may potentially abrogate aspects of remodeling observed in chronic inflammation. The objectives of this application are: to establish the role of S1P2 in initiating inflammatory cell infiltration and propagating inflammation~ to elucidate the newly identified signaling pathway and its relevance to remodeling~ to develop in vivo models targeting the mast cell/S1P/ S1P2 axis in an attempt to prevent features associated with chronic inflammatory disorders. Since targeting individual mediators has failed to prevent sustained inflammation, we anticipate our proposed studies will lead to a better understanding of its underlying mechanisms and pave the way for more mechanistically tailored therapies targeting local regulatory pathways in inflammation with a central role for mast cell expressed S1P2.