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性的结果。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以及从头合成的各种炎症介质，包括组胺、细胞因子和趋化因子，在过敏原交联IgE的高亲和力受体（Fc？RI）。此外，激活的肥大细胞可以释放鞘脂代谢物鞘氨醇-1-磷酸（S1 P），鞘氨醇激酶（SphK）激活后产生。分泌的S1 P可以结合其自身的受体，例如肥大细胞上表达的2型受体（S1 P2）。几种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，这表明它们在该过程中进行了早期干预。我们已经表明，肥大细胞S1 P2是必不可少的早期事件与过敏性炎症的急性体征，其中水肿周围的血管在肺部。水肿促进炎症细胞的随后募集，这也受到血管数量增加的支持，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S1 P2在疾病进展中的作用，并确定它如何导致持续性炎症。 使用药理学，分子和遗传学方法，我们发现了一种新的信号通路，将S1 P2与Stat 3转录因子联系起来，以及破坏这种通路可能潜在地消除慢性炎症中观察到的重塑方面。本申请的目的是：确定S1 P2在启动炎性细胞浸润和传播炎症中的作用，以阐明新鉴定的信号通路及其与重塑的相关性，以开发靶向肥大细胞/S1 P/S1 P2轴的体内模型，以尝试预防与慢性炎性疾病相关的特征。由于针对单个介质未能预防持续的炎症，我们预计我们提出的研究将导致更好地了解其潜在机制，并为针对炎症局部调节途径的更机械定制的治疗铺平道路，其中肥大细胞表达的S1 P2起着核心作用。 公共卫生相关性：慢性炎症在许多疾病中普遍存在，造成与这些耐药疾病相关的大部分医疗保健费用。我们提出，2型受体的多功能介质，鞘氨醇-1-磷酸，其表达的肥大细胞是过敏性疾病的主要反应者，发挥中央功能，在启动和传播的许多功能观察到发炎组织。我们预计，这一创新概念将导致针对慢性炎症局部调节途径的定制疗法，而慢性炎症是无法治愈的。

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. PUBLIC HEALTH RELEVANCE: Chronic inflammation is prevalent in many diseases responsible for the majority of health-care costs associated with these drug-resistant diseases. We are proposing that the type 2 receptor for a multifunctional mediator, sphingosine-1-phosphate, and its expression on mast cells which are primary responders in allergic disorders, exert a central function in initiating and propagating many features observed in inflamed tissues. We anticipate this innovative concept will lead to tailored therapies targeting local regulatory pathways in chronic inflammation for which there is no cure.