Harnessing Inflammatory Macrophages to Thwart Lung Disease Caused by Chronic Ozone Exposure

摘要 不受控制的炎症是哮喘和慢性阻塞性肺疾病的病理生理机制的核心，这些疾病可在下列情况下发展 长期暴露在臭氧中。有证据表明，这些疾病是由于不能充分 化解肺损伤的急性炎症反应。这表明，推动解决 炎症将比抑制持续的、肆无忌惮的炎症更有益。我们的研究是 重点关注巨噬细胞在启动和化解炎症反应方面发挥的关键作用 组织损伤。这种活性由不同的亚群介导，这些亚群被广泛归类为促炎性M1和 预解析M2巨噬细胞。炎症的有效解决取决于新陈代谢的重新编程 巨噬细胞从M1表型到M2表型，这涉及到从糖酵解到氧化的转换 作为能量来源的磷酸化。我们发现，这种重新编程在慢性病后被抑制 臭氧暴露。我们研究的目标是分析抑制巨噬细胞的潜在机制。 重新编程。在最近的研究中，我们发现了法尼醇-X受体(FXR)，它是胆汁中一种重要的核受体 具有抗炎活性的酸代谢在促进M1向M2巨噬细胞转化中起重要作用 在肺部重新编程。臭氧暴露后，巨噬细胞FXR活性下调。这是 与促炎症M1巨噬细胞活性增加和M2促分解活性降低有关 巨噬细胞。我们还发现，调节促炎转录因子NFB的MicroRNAs是 臭氧暴露后巨噬细胞的调节失调。结果，核因子B被持久激活 信号导致肿瘤坏死因子、白介素1和细胞毒性反应氮物种的产生增加。我们 假设这些介质抑制FXR活性，从而阻止核受体的激活 NR4A1，巨噬细胞M1到M2代谢重编程的关键诱导者。为了检验这一假设，我们将(1) 确定慢性臭氧暴露后的持续性炎症和肺部疾病的发展是否 由于前分辨率M2巨噬细胞发育缺陷，并评估这是否由 B在M1巨噬细胞中的持久激活；(2)分析FXR及其靶NR4A1在 慢性臭氧暴露后肺内前分辨M2巨噬细胞的发育；和(3) 确定核因子B的长时间激活是否是由于臭氧诱导调节核因子B的microRNA的变化所致。 这些研究的结果将为慢性臭氧毒性提供新的机制见解，并可能导致 开发新的方法来阻止慢性肺病的发展。

ABSTRACT Uncontrolled inflammation is central to the pathophysiology of asthma and COPD which can develop following chronic exposure to ozone. Evidence suggests that these pathologies are due to an inability to adequately resolve the acute inflammatory response to lung injury. This suggests that promoting the resolution of inflammation will be more beneficial than suppressing persistent unrestrained inflammation. Our studies are focused on macrophages which play a key role in both initiating and resolving inflammatory responses to tissue injury. This activity is mediated by distinct subsets broadly classified as proinflammatory M1 and proresolution M2 macrophages. Effective resolution of inflammation depends on metabolic reprogramming of macrophages from an M1 phenotype to an M2 phenotype, which involves a switch from glycolysis to oxidative phosphorylation as a source of energy. We discovered that this reprogramming is suppressed following chronic ozone exposure. The goal of our studies is to analyze mechanisms underlying suppression of macrophage reprogramming. In recent studies we identified farnesoid-X receptor (FXR), a nuclear receptor important in bile acid metabolism, with anti-inflammatory activity, as important in promoting M1 to M2 macrophage reprogramming in the lung. Following ozone exposure, macrophage FXR activity is downregulated. This is associated with increased activity of proinflammatory M1 macrophages and reduced activity of proresolving M2 macrophages. We also found that microRNAs that regulate the proinflammatory transcription factor NFB are dysregulated in macrophages after ozone exposure. As a consequence, there is protracted activation of NFB signaling resulting in increased production of TNF, IL-1, and cytotoxic reactive nitrogen species. We hypothesize that these mediators suppress FXR activity which prevents activation of the nuclear receptor NR4A1, a key inducer of macrophage M1 to M2 metabolic reprogramming. To test this hypothesis, we will (1) Determine if persistent inflammation following chronic ozone exposure and the development of lung disease is due to defective development of proresolution M2 macrophages, and assess whether this is caused by protracted activation of NFB in M1 macrophages; (2) Analyze the role of FXR and its target NR4A1, in the development of proresolution M2 macrophages in the lung following chronic ozone exposure; and (3) Determine if protracted activation of NFB is due to ozone-induced alterations in microRNAs regulating NFB. Results of these studies will provide new mechanistic insights into chronic ozone toxicity and may lead to the development of new approaches for thwarting the development of chronic lung disease.