cGAS/STING signaling in the regulation of rheumatoid synovial aggression.
cGAS/STING signaling in the regulation of rheumatoid synovial aggression.
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DOI：
10.21037/atm-21-4533
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发表时间：
2022-04
影响因子：
--
通讯作者：
Xu, Hanshi
中科院分区：
文献类型：
--
作者：
Li, Ruiru;Lin, Wei;Kuang, Yu;Wang, Jingnan;Xu, Siqi;Shen, Chuyu;Qiu, Qian;Shi, Maohua;Xiao, Youjun;Liang, Liuqin;Xu, Hanshi
关键词：
成纤维细胞样滑膜细胞（FLS）在促进类风湿关节炎（RA）滑膜侵袭和关节破坏中起关键作用。环GMP-AMP合酶（cGAS）/干扰素基因刺激因子（STING）信号传导在控制一系列细胞生物学过程中起着重要作用。然而，目前尚不清楚cGAS/STING信号是否调节类风湿性滑膜攻击。使用Transwell小室检测细胞迁移和侵袭。采用定量逆转录-聚合酶链反应（qRT-PCR）测定基因表达，并通过蛋白质印迹法检测蛋白质表达。通过2 '，7'-二氯二氢荧光素二乙酸酯（DCFH-DA）探针测量活性氧（ROS）水平。肌动蛋白染色和免疫荧光法分别用于研究板状伪足的形成和核转位。建立重症联合免疫缺陷（SCID）小鼠模型，观察RA FLS在体内的迁移和侵袭。我们的研究结果表明，胞质双链DNA（dsDNA）诱导的cGAS/STING激活促进了RA FLS的体外迁移和侵袭。此外，用cGAS或STING短发夹RNA（shRNA）处理的RA FLS在SCID模型中表现出对软骨的侵袭减少。从机制上讲，我们确定cGAS/STING激活导致线粒体ROS水平增加，从而增加哺乳动物不育20样激酶1（MST 1）的磷酸化，MST 1是Hippo途径的核心组分，随后促进叉头盒1（FOXO 1）的激活。MST 1和FOXO 1的敲除也减少了RA FLS的迁移和侵袭。我们的研究结果表明，cGAS/STING信号传导在调节类风湿性滑膜攻击中具有重要作用，靶向cGAS/STING可能代表RA的一种新的潜在疗法。
Fibroblast-like synoviocytes (FLSs) play a critical role in promoting synovial aggression and joint destruction in rheumatoid arthritis (RA). Cyclic GMP‐AMP synthase (cGAS)/stimulator of interferon gene (STING) signaling plays an important role in controlling a series of cellular biological processes. However, it is still unclear whether cGAS/STING signaling regulates rheumatoid synovial aggression. Cell migration and invasion were detected using a Transwell chamber. Gene expression was measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and protein expression was detected by western blotting. Reactive oxygen species (ROS) levels were measured by 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. F-actin staining and immunofluorescence assays were used to investigate lamellipodia formation and nuclear translocation, respectively. A severe combined immunodeficiency (SCID) mouse model was established to observe the migration and invasion of RA FLSs in vivo. Our results showed that cytosolic double-stranded DNA (dsDNA)-induced cGAS/STING activation promoted the in vitro migration and invasion of RA FLSs. Moreover, RA FLSs treated with cGAS or STING short hairpin RNA (shRNA) exhibited reduced invasion into cartilage in the SCID model. Mechanistically, we determined that cGAS/STING activation leads to increased mitochondrial ROS levels, and thereby increases phosphorylation of mammalian sterile 20-like kinase 1 (MST1), a core component of the Hippo pathway, subsequently promoting activation of forkhead box1 (FOXO1). MST1 and FOXO1 knockdown also diminished the migration and invasion of RA FLSs. Our findings suggest that cGAS/STING signaling has an important role in regulating rheumatoid synovial aggression and that targeting cGAS/STING may represent a novel potential therapy for RA.
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影响因子：
10.5
作者：
Meng Z;Moroishi T;Guan KL
通讯作者：
Guan KL
影响因子：
4.8
作者：
Yuan, Zengqiang;Lehtinen, Maria K.;Bonni, Azad
通讯作者：
Bonni, Azad
影响因子：
39.3
作者：
Yu L;Liu P
通讯作者：
Liu P
DOI：
10.1073/pnas.1505917112
发表时间：
2015-06-09
影响因子：
11.1
作者：
Qi, Qi;Li, Dean Y.;Ye, Keqiang
通讯作者：
Ye, Keqiang
DOI：
10.1038/nrgastro.2016.59
发表时间：
2016-06
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
Hong AW;Meng Z;Guan KL
通讯作者：
Guan KL