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

Omega-3 脂肪酸诱导巨噬细胞 IL-22 信号传导，促进粉尘引起的肺部炎症的消退

• 批准号: 10581016
• 负责人: Tara M Nordgren
• 金额: $ 49.03万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581016
• 关键词: Omega; fatty; acids; induce; macrophage

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.

项目概要 吸入城市、农村和农业环境中的雾化粉尘会引发有害呼吸道 炎症和损伤；随着时间的推移，持续接触这些颗粒物会增加患上这种疾病的风险 炎症性气道疾病。虽然灰尘暴露会对肺部健康产生负面影响，但导致肺部健康的因素 这些持续吸入暴露后的保护作用与对肺部疾病的易感性之间的关系尚不清楚。一个 最近发现一类源自 omega-3 脂肪酸的专门促分解脂质介质 (SPM) 调节肺部炎症、免疫力和修复，并且可能是高膳食纤维有益效果的关键 omega-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 maresin-1 (MaR1) 可减轻急性和重复性器质性气道炎症 粉尘暴露，部分由气道上皮细胞的巨噬细胞激活和促修复活动介导。 我们令人兴奋的新数据表明，omega-3 脂肪酸和 MaR1 可以激活肺部的 IL-22 信号传导 巨噬细胞。 IL-22 信号传导促进粘膜免疫和上皮屏障完整性，及其在 这些生物活性脂质的存在可能是其保护作用的关键。此外，我们的新发现 巨噬细胞中的 IL-22 信号传导挑战了当前有关巨噬细胞激活和调节的教条 途径。该提案的目标是研究 omega-3 脂肪酸在促进促修复 IL-22 中的作用 粉尘暴露后肺部发出的信号。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 来促进颗粒物暴露后的肺恢复 随后促进肺泡巨噬细胞促分辨率极化和肺上皮修复。为了测试这个 假设，在目标 1 中，我们将确定 omega-3 脂肪酸和 IL-22 对肺恢复的影响 灰尘暴露。在目标 2 中，我们将评估 omega-3 脂肪酸和 IL-22 在上皮修复和 粉尘暴露期间的粘膜免疫。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。我们的研究将共同​​确定 omega-3 脂肪酸如何调节易感性 与对灰尘暴露的抵抗力，包括通过激活巨噬细胞 IL- 的新型保护机制 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小说 肺部疾病的治疗策略。