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: 10276478
• 负责人: Tara M Nordgren
• 金额: --
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 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 2021-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10276478
• 关键词: 3-Dimensional; Acute; Agriculture; Air; Air Pollution; Airway Disease; Alveolar; Alveolar Macrophages; Asthma; Attenuated; Cells; Chronic; Coculture Techniques; Data; Diet; Disease; Docosahexaenoic Acids; Dust; Enzymes; Epithelial; Exhibits; Exposure to; Farming environment; Fatty acid glycerol esters; Gene Expression Profiling; Genetic; Goals; Health; Immune; Immune signaling; Immunity; Inflammation; Inflammatory; Inhalation; Inhalation Exposure; Injury; Intake; Investigation; Knock-out; Knowledge; Lead; Leukotrienes; Link; Lipids; Liquid substance; Lung; Lung Inflammation; Lung diseases; Lymphocyte; Macrophage Activation; Mediating; Mediator of activation protein; Modeling; Molecular; Mucosal Immunity; Mus; Omega-3 Fatty Acids; Particulate; Particulate Matter; Pathway interactions; Pharmacology; Physiological; Pneumococcal Infections; Population; Predisposition; Production; Prostaglandins; Publishing; Receptor Signaling; Recommendation; Recovery; Regulation; Reporter; Research; Resolution; Risk; Role; STAT3 gene; Sepsis; Signal Transduction; Smoke; Source; Testing; Time; Tissues; Transgenic Mice; Translations; United States National Institutes of Health; Wildfire; YM1 doxorubicin analog; aerosolized; airway epithelium; airway inflammation; autocrine; base; chronic inflammatory lung disease; desaturase; dietary; epithelial repair; epithelium regeneration; evidence base; improved; in vivo; injured airway; interleukin-22; lipid mediator; macrophage; nano-string; novel; novel therapeutic intervention; paracrine; prevent; protective effect; pulmonary function decline; receptor; repaired; resilience; respiratory; rural environment; scaffold; tissue repair; treatment strategy; urban setting; western diet

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.

项目摘要 从城市，农村和农业环境中吸入尘埃的吸入灰尘会触发有害气道 炎症和伤害；随着时间的流逝，持续接触这些颗粒会增加一个人的发展风险 炎症性气道疾病。虽然尘埃暴露对肺部的健康产生负面影响，但导致的因素 这些持续吸入暴露后，保护与对肺部疾病的敏感性尚不清楚。一个 最近发现了源自omega-3脂肪酸的专门促脂介质（SPM）类 调节肺部炎症，免疫力和修复，可能是饮食高的有益作用的关键 omega-3脂肪酸。我们先前的研究确定omega-3脂肪酸二十六烯酸酸 （DHA）及其脂质代谢物Maresin-1（MAR1）减轻急性和重复有机的气道炎症 灰尘暴露，部分是由气道上皮上的巨噬细胞激活和亲修复活动介导的。 我们令人兴奋的新数据确定omega-3脂肪酸和MAR1可以激活肺中的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激活 这些生物活性脂质的存在可能是其保护作用的关键。此外，我们的小说发现 巨噬细胞中的IL-22信号传导挑战当前关于激活和调节的教条 路径。该提案的目的是研究omega-3脂肪酸在促进Pro-Repair IL-22中的作用 灰尘暴露后肺部发出信号。我们假设Omega-3脂肪酸和SPM促进 通过诱导肺泡巨噬细胞IL-22产生，颗粒物质暴露后的肺恢复 随后，促进肺泡巨噬细胞促链分辨率极化和肺上皮修复。测试这个 假设，在AIM 1中，我们将建立omega-3脂肪酸和IL-22对肺恢复的影响 灰尘曝光。在AIM 2中，我们将评估Omega-3脂肪酸和IL-22在上皮修复和IL-22的作用 灰尘暴露期间的粘膜免疫。在AIM 3中，我们将确定SPM和IL-22信号如何影响肺 巨噬细胞极化。一起，我们的研究将确定omega-3脂肪酸如何调节易感性 与尘埃暴露的韧性相对于韧性，包括通过激活巨噬细胞IL-的新型保护机制 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发现指导小说 肺部疾病的治疗策略。