Frontline Science: Estrogen‐related receptor γ increases poly(I:C)‐mediated type I IFN expression in mouse macrophages,Journal of Leukocyte Biology

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Frontline Science: Estrogen‐related receptor γ increases poly(I:C)‐mediated type I IFN expression in mouse macrophages
Journal of Leukocyte Biology ( IF 3.6 ) Pub Date : 2020-12-08 , DOI: 10.1002/jlb.2hi1219-762r
Ki-Sun Kim ₁ , Don-Kyu Kim ₂ , Soon-Young Na ₁ , Yoon Seok Jung ₁ , Sung Jin Cho _{3,

4} , Jina Kim ₃ , In-Kyu Lee _{4,

5} , Young-Hoon Kim ₆ , Chul-Ho Lee ₆ , Won-Il Jeong ₇ , Eun-Kyeong Jo ₈ , Hueng-Sik Choi ₁

Affiliation

Although type I IFNs (IFN‐I) are important for the innate and adaptive immune responses to suppress viral replication, prolonged IFN‐I signaling in macrophages suppresses the immune response. Nuclear receptor estrogen‐related receptor γ (ERRγ) regulates the transcription of genes involved in endocrine and metabolic functions. However, the role of ERRγ in macrophage immune responses to viruses remains largely unknown. ERRγ expression was significantly induced in mouse bone marrow‐derived macrophages (BMDMs) treated with polyinosinic‐polycytidylic acid (poly(I:C)). Our results indicated that the induction of ERRγ expression by poly(I:C) is mediated through activation of the cytoplasmic dsRNA receptors, retinoic acid‐inducible gene I and melanoma differentiation‐associated protein 5. In BMDMs, overexpression of ERRγ significantly increased gene expression and secretion of the IFN‐I genes, IFN‐α and IFN‐β, whereas abolition of ERRγ significantly attenuated poly(I:C)‐mediated IFN‐I secretion. Chromatin immunoprecipitation assays and mutation analyses of the IFN‐I promoters revealed that ERRγ regulates the transcription of IFN‐α and IFN‐β by binding to a conserved ERR response element in each promoter region. Finally, GSK5182 significantly suppressed poly(I:C)‐mediated induction of IFN‐I gene expression and secretion in BMDMs. Taken together, these findings reveal a previously unrecognized role for ERRγ in the transcriptional control of innate and adaptive immune response to dsRNA virus replication.

中文翻译：

Frontline Science：雌激素相关受体 γ 增加小鼠巨噬细胞中聚 (I:C) 介导的 I 型 IFN 表达

尽管 I 型干扰素 (IFN-I) 对于抑制病毒复制的先天性和适应性免疫反应很重要，但巨噬细胞中长时间的 IFN-I 信号传导会抑制免疫反应。核受体雌激素相关受体 γ (ERRγ) 调节涉及内分泌和代谢功能的基因的转录。然而，ERRγ 在巨噬细胞对病毒的免疫反应中的作用仍然很大程度上未知。在用聚肌苷-聚胞苷酸（poly(I:C)）处理的小鼠骨髓源性巨噬细胞（BMDM）中，ERRγ表达显着诱导。我们的结果表明，poly(I:C) 诱导 ERRγ 表达是通过激活细胞质 dsRNA 受体、视黄酸诱导基因 I 和黑色素瘤分化相关蛋白 5 介导的。在 BMDM 中，ERRγ 的过度表达显着增加了基因表达和 IFN-I 基因、IFN-α 和 IFN-β 的分泌，而 ERRγ 的消除显着减弱了聚 (I:C) 介导的 IFN-I 分泌。染色质免疫沉淀测定和 IFN-I 启动子的突变分析表明，ERRγ 通过与每个启动子区域中保守的 ERR 反应元件结合来调节 IFN-α 和 IFN-β 的转录。最后，GSK5182 显着抑制 BMDM 中聚 (I:C) 介导的 IFN-I 基因表达和分泌诱导。总而言之，这些发现揭示了 ERRγ 在对 dsRNA 病毒复制的先天和适应性免疫反应的转录控制中的先前未被认识的作用。

更新日期：2020-12-08

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