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。虽然粉尘暴露对肺部健康产生负面影响，但导致 在这些持续吸入暴露之后，保护与对肺部疾病的易感性尚不清楚。一 最近发现的一类专门的促分解脂质介质（SPM），来源于ω-3脂肪酸 调节肺部炎症、免疫和修复，可能是高维生素饮食有益效果的关键。 ω-3脂肪酸我们之前的调查发现，ω-3脂肪酸二十二碳六烯酸 (DHA)及其脂质代谢物maresin-1（MaR 1）减轻急性和反复器质性 粉尘暴露，部分由巨噬细胞活化和气道上皮的促修复活性介导。 我们令人兴奋的新数据表明，omega-3脂肪酸和MaR 1可以激活肺中的IL-22信号传导 巨噬细胞IL-22信号转导促进粘膜免疫和上皮屏障完整性， 这些生物活性脂质的存在可能是其保护作用的关键。此外，我们的新发现 巨噬细胞中的IL-22信号传导挑战了目前关于这种激活和调节的教条， 通路这项提案的目的是研究ω-3脂肪酸在促进促修复IL-22中的作用 肺中的信号传导。我们假设omega-3脂肪酸和SPM促进 通过诱导肺泡巨噬细胞产生IL-22， 随后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omega-3脂肪酸和IL-22对以下肺恢复的影响： 粉尘暴露。在目标2中，我们将评估omega-3脂肪酸和IL-22在上皮修复中的作用， 粘膜免疫在粉尘暴露。在目标3中，我们将确定SPM和IL-22信号传导如何影响肺 巨噬细胞极化总之，我们的研究将确定ω-3脂肪酸如何调节易感性 与粉尘暴露的恢复力相比，包括通过激活巨噬细胞IL-1的新保护机制， 22信号传导以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小说 肺部疾病的治疗策略。

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.