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

项目摘要 吸入来自城市、农村和农业环境的气溶胶粉尘可引发有害的 气道炎症和损伤;随着时间的推移，持续暴露于这些颗粒物会增加 患上炎症性气道疾病的风险。虽然灰尘暴露会对 肺健康，有助于保护的因素与肺疾病的易感性， 这些持续的吸入暴露尚不清楚。最近发现的一类特殊的 来自ω-3脂肪酸的促分解脂质介质（SPM）调节肺 炎症，免疫和修复，并且可能是高脂肪饮食有益效果的关键。 ω-3脂肪酸我们之前的调查发现， 二十二碳六烯酸（DHA）及其脂质代谢产物maresin-1（MaR 1）缓解气道 急性和反复接触有机粉尘引起炎症，部分由巨噬细胞介导 对气道上皮的活化和促修复活性。我们令人兴奋的新数据表明， ω-3脂肪酸和MaR 1可以激活肺巨噬细胞中的IL-22信号传导。IL-22 信号传导促进粘膜免疫和上皮屏障完整性，并且其在 这些生物活性脂质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信号传导的发现挑战了目前关于激活 和调节这一途径。这项提案的目的是调查欧米茄-3的作用 脂肪酸促进粉尘暴露后肺中的促修复IL-22信号传导。我们 假设omega-3脂肪酸和SPM促进了微粒吸入后肺恢复 通过诱导肺泡巨噬细胞产生IL-22， 促进肺泡巨噬细胞前分辨率极化和肺上皮修复。为了验证这一 假设，在目标1中，我们将确定ω-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脂肪酸的作用， IL-22在粉尘暴露后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信号传导如何影响肺巨噬细胞极化。我们的研究将 确定ω-3脂肪酸如何调节对灰尘暴露的敏感性与恢复力， 包括通过激活巨噬细胞IL-22信号传导促进 组织修复和粘膜免疫。我们希望我们的研究结果能够指导新的治疗方法 肺疾病的治疗策略

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.