Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Florida, Gainesville, FL, United States.
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, United States.
Front Immunol. 2018 Feb 2;9:135. doi: 10.3389/fimmu.2018.00135. eCollection 2018.
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 () and vs. mice treated with mineral oil, a control inflammatory oil that does not cause lupus. Glycolytic metabolism (extracellular flux assays) and 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.
The LXR agonist T0901317 inhibited type I interferon and increased ABCA1 in lupus patients' monocytes and in murine peritoneal macrophages. , 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.
从组织中清除凋亡细胞的 CD138 吞噬性巨噬细胞的生成具有替代（M2）表型，而狼疮患者这种生成存在缺陷。肝 X 受体-α（LXRα）是一种氧化固醇调节的转录因子，可促进胆固醇逆向转运和替代（M2）巨噬细胞激活。相反，低氧诱导因子 1-α（HIF1α）促进经典（M1）巨噬细胞激活。本研究旨在探讨使用 LXR 激动剂增强 M2 样巨噬细胞的生成是否可以治疗狼疮。从 pristane 处理的小鼠的腹腔巨噬细胞中具有 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），以及低表达 LXRα 调节的基因 ATP 结合盒亚家族 A 成员 1（）和 与用矿物油（一种不会引起狼疮的对照炎性油）处理的小鼠相比。糖酵解代谢（细胞外通量测定）和 表达在 pristane 处理的小鼠（M1 样）中较高，而氧化代谢和 LXRα 表达在矿物油处理的小鼠（M2 样）中较高。同样，狼疮患者的单核细胞表现出低 LXRα/ABCA1 和高 HIF1α与对照相比。
LXR 激动剂 T0901317 抑制 I 型干扰素并增加狼疮患者单核细胞和小鼠腹腔巨噬细胞中的 ABCA1。 ，T0901317 诱导 M2 样巨噬细胞极化并保护小鼠免于弥漫性肺泡出血（DAH），这是狼疮的一种常见致命并发症。我们得出结论，使用 LXR 激动剂纠正狼疮特有的巨噬细胞分化异常可预防鼠狼疮的靶器官损伤（DAH）。LXR 激动剂还降低了人类狼疮单核细胞中炎症细胞因子的产生，表明这些药物可能在狼疮的药物治疗中发挥作用。
