已知炎性巨噬细胞有助于臭氧毒性。法尼醇X受体(FXR)是参与调节胆汁酸和脂质稳态的核受体;它还通过抑制巨噬细胞NF-κB发挥抗炎活性。在这里,我们分析了FXR在臭氧暴露后调节肺巨噬细胞活化中的作用.用臭氧(0.8ppm,3h)导致肺中促炎(F4/80+CD11c+CD11b+Ly6CHi)和抗炎(F4/80+CD11c+CD11b+Ly6CLo)巨噬细胞增加。与WT小鼠相比,FXR-/-小鼠中促炎巨噬细胞的积累增加;然而,正如精氨酸酶和甘露糖受体表达减少所反映的那样,抗炎巨噬细胞活化被钝化,反应与Nur77下降相关。这与长期的氧化应激有关,由肺中的4-羟基壬烯醛修饰蛋白测量。FXR的丢失伴随着肺NF-κB活性及其靶标的长期增加,响应臭氧的诱导型一氧化氮合酶。Tnf-α的水平,IL-1β,相对于WT小鼠,FXR-/-的肺中Ccr2,Ccl2,Cx3cr1和Cx3cl1也增加;相反,调节脂质稳态的基因,包括Lxrα,Apoe,Vldlr,Abcg1和Abca1下调,与臭氧接触无关。在FXR-/-小鼠中,臭氧导致肺磷脂总量增加,对SP-B或SP-D无影响血脂异常与臭氧引起的呼气末正压依赖性准静压容积曲线的钝化相关,表明FXR-/-小鼠的肺变硬。这些发现将FXR鉴定为臭氧暴露后巨噬细胞活化的调节剂,表明FXR配体可用于减轻由肺刺激物诱导的炎症和氧化应激。
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+Ly6CHi) and anti-inflammatory (F4/80+CD11c+CD11b+Ly6CLo) 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.