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

项目总结 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上疾病的风险 炎症性呼吸道疾病。虽然接触粉尘对肺部健康有负面影响，但导致 这些持续的吸入暴露对肺部疾病的保护作用和易感性尚不清楚。一个 最近发现的一类源于omega-3脂肪酸的专门化促分解脂质介体(SPM) 调节肺部炎症、免疫和修复，这可能是高营养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及其脂质代谢物Marein-1(MaR1)减轻急性反复器质性呼吸道炎症 粉尘暴露，部分是通过激活巨噬细胞和促进呼吸道上皮修复活动来调节的。 我们令人兴奋的新数据表明，omega-3脂肪酸和MaR1可以激活肺中的IL-22信号 巨噬细胞。IL-22信号促进黏膜免疫和上皮屏障完整性，并激活 这些生物活性脂类的存在可能是其保护作用的关键。此外，我们的新发现 巨噬细胞中的IL-22信号对当前关于其激活和调节的教条提出了挑战 路径。这项提案的目标是研究omega-3脂肪酸在促进IL-22修复方面的作用 暴露于粉尘后肺部的信号。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促进颗粒物暴露后肺功能恢复 随后促进肺泡巨噬细胞前分辨极化和肺上皮修复。为了测试这一点 假设，在目标1中，我们将确定omega-3脂肪酸和IL-22对下列肺恢复的影响 暴露在粉尘中。在目标2中，我们将评估omega-3脂肪酸和IL-22在上皮修复和修复中的作用。 接尘过程中的粘膜免疫功能。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。总之，我们的研究将确定omega-3脂肪酸如何调节易感性 对粉尘暴露的弹性，包括一种新的保护机制，通过激活巨噬细胞IL-2 22发出信号，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.