Liver X Receptor Agonist Therapy Prevents Diffuse Alveolar Hemorrhage in Murine Lupus by Repolarizing Macrophages.
Liver X Receptor Agonist Therapy Prevents Diffuse Alveolar Hemorrhage in Murine Lupus by Repolarizing Macrophages.
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DOI：
10.3389/fimmu.2018.00135
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发表时间：
2018
影响因子：
7.3
通讯作者：
Reeves WH
中科院分区：
文献类型：
--
作者：
Han S;Zhuang H;Shumyak S;Wu J;Xie C;Li H;Yang LJ;Reeves WH
具有从组织中清除凋亡细胞的替代（M2）表型的CD 138+吞噬巨噬细胞的产生在狼疮中是有缺陷的。肝脏X受体-α（LXRα）是一种氧固醇调节的转录因子，可促进胆固醇逆向转运和替代（M2）巨噬细胞活化。相反，缺氧诱导因子1-α（HIF 1 α）促进经典（M1）巨噬细胞活化。本研究的目的是观察是否可以通过使用LXR激动剂增强M2样巨噬细胞的产生来治疗狼疮。与矿物油（一种不会引起狼疮的对照炎症油）处理的小鼠相比，降植烷处理小鼠的腹膜巨噬细胞具有M1表型、高HIFα调节的磷酸果糖激酶和TNFα表达（定量PCR，流式细胞术）以及低LXRα调节的基因ATP结合盒亚家族A成员1（Abca 1）和IL 10表达。降植烷处理小鼠（M1样）的糖酵解代谢（细胞外流量测定）和Hif 1a表达较高，而矿物油处理小鼠（M2样）的氧化代谢和LXRα表达较高。同样，与对照组相比，狼疮患者的单核细胞表现出低LXRα/ABCA 1和高HIF 1 α。LXR激动剂T0901317在狼疮患者的单核细胞和小鼠腹腔巨噬细胞中抑制I型干扰素并增加ABCA 1。在体内，T0901317诱导M2样巨噬细胞极化，并保护小鼠免受弥漫性肺泡出血（DAH），这是狼疮的一种致命并发症。我们的结论是，终末器官损伤（DAH）在小鼠狼疮可以预防使用LXR激动剂，以纠正巨噬细胞分化异常狼疮的特点。LXR激动剂也减少人类狼疮单核细胞的炎性细胞因子产生，表明这些药物可能在狼疮的药物治疗中发挥作用。
The generation of CD138+ phagocytic macrophages with an alternative (M2) phenotype that clear apoptotic cells from tissues is defective in lupus. Liver X receptor-alpha (LXRα) is an oxysterol-regulated transcription factor that promotes reverse cholesterol transport and alternative (M2) macrophage activation. Conversely, hypoxia-inducible factor 1-α (HIF1α) promotes classical (M1) macrophage activation. The objective of this study was to see if lupus can be treated by enhancing the generation of M2-like macrophages using LXR agonists. Peritoneal macrophages from pristane-treated mice had an M1 phenotype, high HIFα-regulated phosphofructokinase and TNFα expression (quantitative PCR, flow cytometry), and low expression of the LXRα-regulated gene ATP binding cassette subfamily A member 1 (Abca1) and Il10 vs. mice treated with mineral oil, a control inflammatory oil that does not cause lupus. Glycolytic metabolism (extracellular flux assays) and Hif1a expression were higher in pristane-treated mice (M1-like) whereas oxidative metabolism and LXRα expression were higher in mineral oil-treated mice (M2-like). Similarly, lupus patients’ monocytes exhibited low LXRα/ABCA1 and high HIF1α vs. controls. The LXR agonist T0901317 inhibited type I interferon and increased ABCA1 in lupus patients’ monocytes and in murine peritoneal macrophages. In vivo, T0901317 induced M2-like macrophage polarization and protected mice from diffuse alveolar hemorrhage (DAH), an often fatal complication of lupus. We conclude that end-organ damage (DAH) in murine lupus can be prevented using an LXR agonist to correct a macrophage differentiation abnormality characteristic of lupus. LXR agonists also decrease inflammatory cytokine production by human lupus monocytes, suggesting that these agents may be have a role in the pharmacotherapy of lupus.