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

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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 NFκB are dysregulated in macrophages after ozone exposure. As a consequence, there is protracted activation of NFκB signaling resulting in increased production of TNFα, IL-1β, 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 NFκB 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 NFκB is due to ozone-induced alterations in microRNAs regulating NFκB. 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.