IRF-8/miR-451a regulates M-MDSC differentiation via the AMPK/mTOR signal pathway during lupus development.
IRF-8/miR-451a regulates M-MDSC differentiation via the AMPK/mTOR signal pathway during lupus development.
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IRF-8/miR-451a 在狼疮发育过程中通过 AMPK/mTOR 信号通路调节 M-MDSC 分化
DOI：
10.1038/s41420-021-00568-z
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发表时间：
2021-07-16
影响因子：
7
通讯作者：
Hou Y
中科院分区：
文献类型：
--
作者：
Shi G;Li D;Zhang D;Xu Y;Pan Y;Lu L;Li J;Xia X;Dou H;Hou Y
系统性红斑狼疮（SLE）是一种慢性全身性自身免疫性疾病。骨髓源性抑制细胞（MDSC）已被发现参与调节SLE的发展。然而，关于MDSC亚群与导致MDSC异常扩增的因素之间的关联知之甚少。这项研究发现，在降植烷诱导的狼疮小鼠中，M-MDSC的百分比增加。Toll样受体（TLR）7信号的激活和高水平的干扰素-α（IFN-α）促进M-MDSC的体外分化。此外，AMP活化蛋白激酶（AMPK）激动剂二甲双胍和两种雷帕霉素（mTOR）抑制剂（INK 128和雷帕霉素）抑制狼疮小鼠中M-MDSC的百分比以及TLR 7和IFN-α诱导的骨髓（BM）体外分化为MDSC。在机制方面，通过RNA测序进行全基因组转录组分析，揭示转录因子IRF-8在从降植烷诱导的狼疮小鼠分离的M-MDSC中的表达高于对照小鼠。IRF-8在TLR 7和IFN-α体外诱导骨髓向MDSC分化中起关键作用。此外，干扰素（IFN）调节因子8（IRF-8）在M-MDSC分化中被miR-451 a靶向。值得注意的是，二甲双胍修饰的M-MDSC可以缓解降植烷诱导的狼疮小鼠的狼疮症状。这些发现揭示了在狼疮发展过程中通过AMPK/mTOR信号通路将IRF-8/miR-451 a与M-MDSC分化联系起来的新机制。本研究为靶向M-MDSCs治疗SLE提供了重要参考。
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease. Myeloid-derived suppressor cells (MDSCs) have been found to be involved in the regulation of SLE development. However, little is known about the association between MDSC subsets and the factors that draw MDSCs into abnormal expansion. This study found that the percentage of M-MDSCs increased in mice with pristane-induced lupus. Toll-like receptor (TLR)7 signal activation and high interferon-α (IFN-α) level promoted M-MDSC differentiation in vitro. Moreover, both AMP-activated protein kinase (AMPK) agonist metformin and two mammalian targets of rapamycin (mTOR) inhibitors (INK128 and rapamycin) inhibited the percentage of M-MDSCs in lupus mice as well as in the TLR7- and IFN-α-induced bone marrow (BM) differentiation into MDSCs in vitro. In terms of mechanism, whole-genome transcriptome profiling was performed by RNA sequencing, revealing that the expression of the transcription factor IRF-8 was higher in M-MDSCs isolated from pristane-induced lupus mice, compared with control mice. IRF-8 was identified to be crucial for TLR7- and IFN-α-induced BM differentiation into MDSCs in vitro. Furthermore, interferon (IFN) regulatory factor8 (IRF-8) was targeted by miR-451a in M-MDSC differentiation. Of note, metformin-modified M-MDSCs could relieve lupus symptoms in pristane-induced lupus mice. The findings revealed a novel mechanism linking IRF-8/miR-451a to M-MDSC differentiation via the AMPK/mTOR signal pathway during lupus development. This study might provide an important reference for SLE therapy by targeting M-MDSCs.
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影响因子：
13.3
作者：
Lourenco, Elaine V.;Wong, Maida;Skaggs, Brian J.
通讯作者：
Skaggs, Brian J.
影响因子：
4.5
作者：
Cunninghame Graham DS;Morris DL;Bhangale TR;Criswell LA;Syvänen AC;Rönnblom L;Behrens TW;Graham RR;Vyse TJ
通讯作者：
Vyse TJ
DOI：
10.4049/jimmunol.1402412
发表时间：
2015-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Paschall AV;Zhang R;Qi CF;Bardhan K;Peng L;Lu G;Yang J;Merad M;McGaha T;Zhou G;Mellor A;Abrams SI;Morse HC 3rd;Ozato K;Xiong H;Liu K
通讯作者：
Liu K
影响因子：
4.4
作者：
Lee, Seon-Yeong;Moon, Su-Jin;Cho, Mi-La
通讯作者：
Cho, Mi-La
影响因子：
50.3
作者：
Strauss, Laura;Sangaletti, Sabina;Sica, Antonio
通讯作者：
Sica, Antonio