Control of Pulmonary Inflammation by Leukotriene E4

摘要/概要 本申请继续支持的重点是半胱氨酰白三烯 （cysLTs），一类有效的脂质炎症介质，促进2型（嗜酸性）免疫病理学（T2 I） 这是普遍和负担沉重的呼吸道疾病的基础，包括哮喘和慢性鼻窦炎， 鼻息肉（CRSwNP）。该提案测试了白三烯E4（LTE 4）启动呼吸T2 I的假设 通过3型cysLT受体（CysLT 3R）和核苷酸信号传导至P2 Y2受体， 刷状细胞（BrCs）。第二个假设是LTE 4诱导的BrC激活增强了第2组的激活。 先天性淋巴样细胞（ILC 2）和2型细胞因子的产生，通过IL-25和 内源性LTC 4。第三个假设是IL-25驱动的嗜酸性粒细胞募集提供了一个库， 的LTC 4驱动的血小板衍生的IL-33，以递增地激活ILC 2和MC，进一步扩增T2 I及其受体。 后果，包括上游BrC扩张。该提案使用了一种新的转基因小鼠， 离体方法和独特的模型来剖析cysLT串联作用的复杂途径 下游的上皮扰动的白三烯E4，最稳定的cysLT，激活MC，有力地引发 ILC 2激活，并诱导严重的免疫病理学。这些研究试图解释选择性 哮喘受试者对白三烯E4的高反应性，并通过 选择性靶向CysLT 1 R以外的受体。

Abstract/Summary This application for continuing support focuses on the mechanisms by which the cysteinyl leukotrienes (cysLTs), a class of potent lipid inflammatory mediators, facilitate type 2 (eosinophilic) immunopathology (T2I) that underlies prevalent and burdensome respiratory diseases, including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). The proposal tests the hypothesis that leukotriene E4 (LTE4) initiates respiratory T2I through engagement of the type 3 cysLT receptor (CysLT3R) and nucleotide signaling to P2Y2 receptors on brush cells (BrCs). A second hypothesis is that LTE4-induced BrC activation elicits activation of group 2 innate lymphoid cells (ILC2s) and type 2 cytokine generation through synergistic actions of IL-25 and endogenously generated LTC4. A third hypothesis is that IL-25-driven eosinophil recruitment provides a pool of LTC4-driven platelet-derived IL-33 to incrementally activate ILC2s and MCs, further amplifying T2I and its consequences, including upstream BrC expansion. The proposal uses a combination of novel transgenic mice, ex vivo approaches, and unique models to dissect a complex pathway by which cysLTs act in series downstream of epithelial perturbation by leukotriene E4, the most stable cysLT, to activate MC, potently elicit ILC2 activation, and induce severe immunopathology. The studies seek to explain the selective hyperresponsiveness of asthmatic subjects to leukotriene E4, and to develop therapeutic strategies through the selective targeting of receptors other than CysLT1R.