Omega-3 fatty acids induce macrophage IL-22 signaling to promote resolution of dust-induced lung inflammation

项目摘要 吸入城市、农村和农业环境中的雾化粉尘会引发有害的 呼吸道炎症和损伤；随着时间的推移，持续暴露在这些颗粒物中会增加 患炎症性呼吸道疾病的风险。而粉尘暴露则会产生负面影响 肺健康，有助于保护的因素与以下肺部疾病的易感性 这些持续的吸入暴露尚不清楚。最近发现的一类专门的 Omega-3脂肪酸衍生的促分解脂介质(SPM)调节肺功能 炎症、免疫和修复，这可能是高摄入量饮食有益效果的关键。 欧米茄-3脂肪酸。我们之前的研究发现，omega-3脂肪酸 二十二碳六烯酸(DHA)及其脂类代谢物Marein-1(MaR1)对呼吸道的作用 急性和重复接触有机粉尘引起的炎症，部分由巨噬细胞介导 对呼吸道上皮细胞的激活和修复活性。我们令人振奋的新数据表明 Omega-3脂肪酸和MaR1可以激活肺巨噬细胞中的IL-22信号。IL-22 信号转导促进黏膜免疫和上皮屏障完整性，并促进其激活。 这些生物活性脂类的存在可能是其保护作用的关键。此外，我们的小说 巨噬细胞中IL-22信号的发现挑战了目前关于激活的教条 以及对这一途径的调控。这项提案的目标是研究omega-3的作用 脂肪酸在粉尘暴露后促进肺内IL-22信号修复中的作用。我们 假设omega-3脂肪酸和SPM促进颗粒物后的肺恢复 通过诱导肺泡巨噬细胞产生IL-22而导致的物质暴露 促进肺泡巨噬细胞前分解极化和肺上皮修复。为了测试这一点 假设，在目标1中，我们将建立omega-3脂肪酸和IL-22对肺的影响 粉尘暴露后的恢复。在目标2中，我们将评估omega-3脂肪酸和 接尘过程中IL-22在上皮修复和粘膜免疫中的作用在目标3中，我们将确定 SPM和IL-22信号如何影响肺巨噬细胞极化。共同努力，我们的研究将 确定omega-3脂肪酸如何调节对粉尘暴露的敏感性和韧性， 包括一种新的保护机制，通过激活巨噬细胞IL-22信号促进 组织修复和粘膜免疫。我们希望我们的研究结果能指导新的治疗方法。 肺部疾病的策略。

Project Summary Inhalation of aerosolized dusts from urban, rural, and farming environments can trigger harmful airway inflammation and injury; over time, continual exposure to these particulates increases one’s risk for developing inflammatory airway diseases. While dust exposures negatively impact lung health, factors contributing to protection versus susceptibility to lung disease following these continual inhalational exposures are unclear. A recently discovered class of specialized pro-resolving lipid mediators (SPM) derived from omega-3 fatty acids regulate lung inflammation, immunity, and repair, and are likely key to the beneficial effects of diets high in omega-3 fatty acids. Our previous investigations identified that the omega-3 fatty acid docosahexaenoic acid (DHA) and its lipid metabolite maresin-1 (MaR1) mitigate airway inflammation from acute and repetitive organic dust exposure, mediated in part by macrophage activation and pro-repair activities on the airway epithelium. Our exciting new data identify that omega-3 fatty acids and MaR1 can activate IL-22 signaling in lung macrophages. IL-22 signaling promotes mucosal immunity and epithelial barrier integrity, and its activation in the presence of these bioactive lipids may be key to their protective effects. Furthermore, our novel finding of IL-22 signaling in macrophages challenges current dogma regarding the activation and regulation of this pathway. The goal of this proposal is to investigate the role of omega-3 fatty acids in promoting pro-repair IL-22 signaling in the lung following dust exposures. We hypothesize that omega-3 fatty acids and SPM promote lung recovery following particulate matter exposures by inducing alveolar macrophage IL-22 production that subsequently promotes alveolar macrophage pro-resolution polarization and lung epithelial repair. To test this hypothesis, in Aim 1, we will establish the impact of omega-3 fatty acids and IL-22 on lung recovery following dust exposure. In Aim 2, we will evaluate the role of omega-3 fatty acids and IL-22 in epithelial repair and mucosal immunity during dust exposure. In Aim 3, we will identify how SPM and IL-22 signaling impacts lung macrophage polarization. Together, our studies will identify how omega-3 fatty acids modulate susceptibility versus resilience to dust exposures, including a novel protective mechanism via activation of macrophage IL-22 signaling to promote tissue repair and mucosal immunity. We expect our studies’ findings to guide novel treatment strategies for lung disease.