药理LRH-1 / Nr5a2抑制作用可限制巨噬细胞和相关实验性肝炎中促炎性细胞因子的产生。,Cell Death & Disease

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药理LRH-1 / Nr5a2抑制作用可限制巨噬细胞和相关实验性肝炎中促炎性细胞因子的产生。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-02-28 , DOI: 10.1038/s41419-020-2348-9
Juliane Schwaderer ₁ , Truong San Phan ₁ , Astrid Glöckner ₁ , Johannes Delp _{2,

3} , Marcel Leist ₂ , Thomas Brunner ₁ , M Eugenia Delgado ₁

Affiliation

肝受体同源物1（LRH-1，Nr5a2）是一种主要在内胚层组织中表达的孤儿核受体，已对其广泛的生理作用进行了研究。LRH-1与肝细胞的分化和增殖以及葡萄糖，脂质和胆汁酸的代谢有关。此外，越来越多的证据强调了其在肠道上皮中通过糖皮质激素合成在免疫调节过程中的作用。尽管已经阐明了LRH-1在免疫细胞中的直接功能，但是最近已经报道了LRH-1在调节巨噬细胞分化中的作用。在这项研究中，我们旨在调查LRH-1在巨噬细胞中促炎性细胞因子产生调控中的作用。我们的数据表明，药理学抑制作用以及LRH-1敲除，大大减少了脂多糖（LPS）诱导的巨噬细胞系RAW 264.7细胞以及原代鼠巨噬细胞促炎性细胞因子的产生。发现该抑制作用与LRH-1调节的细胞增殖的缺陷或LRH-1抑制剂的毒性作用无关。相比之下，LRH-1抑制通过下调LRH-1靶标葡萄糖激酶和谷氨酰胺酶2降低线粒体ATP的产生和巨噬细胞的代谢，从而削弱LPS诱导的巨噬细胞活化。有趣的是，在肝炎的巨噬细胞和TNF依赖性小鼠模型中，LRH-1的体内药理抑制作用还导致肿瘤坏死因子（TNF）的产生减少，以及肝脏损伤的减少。值得注意的是，尽管肝细胞表达高水平的LRH-1，LRH-1本身的药理抑制作用并未引起任何明显的肝损害。因此，这项研究提出LRH-1作为炎症性疾病的新兴治疗靶标，特别是在巨噬细胞和细胞因子决定炎症程度的地方。

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Pharmacological LRH-1/Nr5a2 inhibition limits pro-inflammatory cytokine production in macrophages and associated experimental hepatitis.

Liver receptor homolog-1 (LRH-1, Nr5a2) is an orphan nuclear receptor mainly expressed in tissues of endodermal origin, where its physiological role has been extensively studied. LRH-1 has been implicated in liver cell differentiation and proliferation, as well as glucose, lipid, and bile acid metabolism. In addition, increasing evidence highlights its role in immunoregulatory processes via glucocorticoid synthesis in the intestinal epithelium. Although the direct function of LRH-1 in immune cells is fairly elucidated, a role of LRH-1 in the regulation of macrophage differentiation has been recently reported. In this study, we aimed to investigate the role of LRH-1 in the regulation of pro-inflammatory cytokine production in macrophages. Our data demonstrate that pharmacological inhibition, along with LRH-1 knockdown, significantly reduced the lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines in the macrophage line RAW 264.7 cells, as well as in primary murine macrophages. This inhibitory effect was found to be independent of defects of LRH-1-regulated cell proliferation or toxic effects of the LRH-1 inhibitors. In contrast, LRH-1 inhibition reduced the mitochondrial ATP production and metabolism of macrophages through downregulation of the LRH-1 targets glucokinase and glutminase-2, and thus impairing the LPS-induced macrophage activation. Interestingly, in vivo pharmacological inhibition of LRH-1 also resulted in reduced tumor necrosis factor (TNF) production and associated decreased liver damage in a macrophage- and TNF-dependent mouse model of hepatitis. Noteworthy, despite hepatocytes expressing high levels of LRH-1, pharmacological inhibition of LRH-1 per se did not cause any obvious liver damage. Therefore, this study proposes LRH-1 as an emerging therapeutic target in the treatment of inflammatory disorders, especially where macrophages and cytokines critically decide the extent of inflammation.

更新日期：2020-02-28

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