HIF-1α通过下调ALKBH7表达介导线粒体损伤,促进类风湿关节炎FLS异常活化。

IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Han Wang, Yu-Chen Zhao, Li Xu, Tian-Jing Zhang, Liang-Hu Liu, Meng-Qi Zhou, Han Zhang, Yin-Ning Yang, Pin Pan, Lin Jin, Zi-Wei Zhang, Xian-Zheng Zhang, Ling-Ling Zhang
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引用次数: 0

摘要

类风湿性关节炎(RA)是一种以滑膜炎症和进行性关节破坏为特征的自身免疫性疾病。现有证据表明,缺氧可能有助于类风湿性关节炎的病理,但具体机制尚不清楚。本研究探讨缺氧诱导因子(HIF-1α)参与RA病理过程的分子机制。我们的初步结果表明,缺氧通过诱导线粒体损伤激活cGAS-STING信号,从而刺激成纤维细胞样滑膜细胞(FLS)的激活,而沉默HIF-1α可以有效抑制cGAS-STING信号。与此相一致的是,HIF-1α缺乏显著减轻了胶原诱导关节炎(CIA)小鼠的症状。RNA-Seq和CUT-Tag分析显示,HIF-1α通过作用于19号染色体6372400-6372578上的ALKBH7启动子位点,下调AlkB同源物7 (ALKBH7)的表达。通过双荧光素酶报告基因分析,我们发现ACCGTGGC是HIF-1α直接结合的基序。随后,我们证明了ALKBH7的敲低可诱导线粒体损伤,并通过下调UQCRC2的表达激活cGAS-STING信号。相反,ALKBH7的过表达可以抵抗缺氧诱导的线粒体损伤和FLS激活。综上所述,HIF-1α通过下调ALKBH7的表达从而促进FLS的激活而引发线粒体损伤,这可能是缺氧参与RA病理过程的分子机制。缺氧通过诱导线粒体损伤促进FLS的激活,线粒体损伤随后激活cGAS-STING信号。在机制上,HIF-1α通过下调ALKBH7的表达靶标方式触发线粒体损伤。此外,与其他复合物相反,ALKBH7的缺失主要通过下调UQCRC2导致缺氧条件下的线粒体损伤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
HIF-1α mediates mitochondrial damage by down-regulating ALKBH7 expression to promote the aberrant activation of FLS in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and progressive joint destruction. Existing evidence indicates that hypoxia potentially contributes to the pathology of RA, though the specific mechanism remains unidentified. In this study, we explored the molecular mechanism through which the hypoxia-inducible factor (HIF-1α) contributed to the pathological process of RA. Our preliminary results suggested that hypoxia stimulates the activation of fibroblast-like synoviocytes (FLS) by inducing mitochondrial damage to activate cGAS-STING signaling, which can be effectively inhibited by silencing HIF-1α. In line with this, HIF-1α deficiency significantly alleviated the symptoms of collagen-induced arthritis (CIA) mice. RNA-Seq and CUT-Tag analysis revealed that HIF-1α down-regulated the expression of AlkB homologue 7 (ALKBH7) by acting on the ALKBH7 promoter site on chromosome 19 6372400-6372578. Using dual luciferase reporter analysis, we identified that ACCGTGGC as the motif to which HIF-1α bound directly. Subsequently, we demonstrated that knockdown of ALKBH7 induces mitochondrial damage and activates cGAS-STING signaling by downregulating the expression of UQCRC2. Conversely, overexpression of ALKBH7 could resist hypoxia-induced mitochondrial damage and FLS activation. In conclusion, HIF-1α triggers mitochondrial damage by downregulating the expression of ALKBH7 thereby promoting FLS activation, which may be the molecular mechanism by which hypoxia is involved in the pathological process of RA. Hypoxia promotes the activation of FLS through the induction of mitochondrial damage, which subsequently activates cGAS-STING signaling. Mechanistically, HIF-1α triggers mitochondrial damage by downregulating the expression of ALKBH7 in a target manner. Furthermore, the deletion of ALKBH7 leads to mitochondrial damage under hypoxic conditions, primarily through the downregulation of UQCRC2, as opposed to other complexes.

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来源期刊
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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