Regulation of Lung Macrophage Activation and Oxidative Stress Following Ozone Exposure by Farnesoid X Receptor. (10th September 2020)

• Record Type: Journal Article
• Authors: Francis, Mary; Guo, Grace; Kong, Bo; Abramova, Elena V; Cervelli, Jessica A; Gow, Andrew J; Laskin, Jeffrey D; Laskin, Debra L
• Is Part Of: Toxicological sciences. Volume 177:Number 2(2020)
• Page Start: 441
• Page End: 453
• Publication Date: 2020-09-10
• Subjects: ozone -- inflammatory macrophages -- FXR -- pulmonary lipids -- oxidative stress; Toxicology -- Periodicals; Toxicology -- Periodicals; Toxicology; Periodicals; 615.9
• DOI: 10.1093/toxsci/kfaa111
• Languages: English
• ISSNs: 1096-6080

Abstract

Abstract: Inflammatory macrophages are known to contribute to ozone toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating bile acid and lipid homeostasis; it also exerts anti-inflammatory activity by suppressing macrophage NF-κB. Herein, we analyzed the role of FXR in regulating macrophage activation in the lung following ozone exposure. Treatment of wild-type (WT) mice with ozone (0.8 ppm, 3 h) resulted in increases in proinflammatory (F4/80 + CD11c + CD11b + Ly6C Hi ) and anti-inflammatory (F4/80 + CD11c + CD11b + Ly6C Lo ) macrophages in the lung. The accumulation of proinflammatory macrophages was increased in FXR −/− mice compared with WT mice; however, anti-inflammatory macrophage activation was blunted as reflected by reduced arginase and mannose receptor expression, a response correlated with decreased Nur77 . This was associated with prolonged oxidative stress, as measured by 4-hydroxynonenal-modified proteins in the lung. Loss of FXR was accompanied by protracted increases in lung NF-κB activity and its target, inducible nitric oxide synthase in response to ozone. Levels of Tnf-α, Il-1β, Ccr2, Ccl2, Cx3cr1, and Cx3cl1 were also increased in lungs of FXR −/− relative to WT mice; conversely, genes regulating lipid homeostasis including Lxrα, Apoe, Vldlr, Abcg1, and Abca1 were downregulated, irrespective of ozone exposure. In FXR −/− mice, ozone caused an increase in total lung phospholipids, with no effect on SP-B or SP-D. Dyslipidemia was correlated with blunting of ozone-induced increases in positive end-expiratory pressure-dependent quasi-static pressure volume curves indicating a stiffer lung in FXR −/− mice. These findings identify FXR as a regulator of macrophage activation following ozone exposure suggesting that FXR ligands may be useful in mitigating inflammation and oxidative stress induced by pulmonary irritants.