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

描述（由申请人提供）：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，是炎症的主要反应者，通过释放预先形成的和重新合成的各种炎症介质，包括组胺、细胞因子和趋化因子，在高亲和力IgE受体的过敏原交联上（Fc?RI）。此外，激活的肥大细胞可以释放鞘脂代谢产物鞘鞘醇-1-磷酸（S1P），由鞘鞘醇激酶（SphK）激活产生。分泌的S1P可与自身受体结合，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在炎症灶中建立了肥大细胞数量的早期增加，这表明它们在这一过程中的早期干预。我们已经证明肥大细胞S1P2对过敏性炎症的急性症状相关的早期事件至关重要，其中包括肺部血管周围的水肿。水肿促进随后的炎症细胞募集，也有利于血管数量的增加，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小鼠模型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炎症。利用药理学、分子和遗传学方法，我们发现了一条连接S1P2和Stat3转录因子的新信号通路，以及如何破坏这条通路可能潜在地消除慢性炎症中观察到的重塑方面。本应用的目的是：确定S1P2在启动炎症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，建立针对肥大细胞/S1P/ S1P2轴的体内模型，试图预防与慢性炎症疾病相关的特征。由于靶向单个介质未能阻止持续炎症，我们预计我们提出的研究将导致更好地了解其潜在机制，并为针对炎症中的局部调节途径（肥大细胞表达S1P2的核心作用）的更机械定制治疗铺平道路。

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.