Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory.
Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory.
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长期接触TNF通过建立长期的炎症记忆来重新编程成纤维细胞样的滑膜细胞中的细胞信号通路。
DOI：
10.1038/s41598-020-77380-9
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发表时间：
2020-11-20
影响因子：
4.6
通讯作者：
Bhattaram P
中科院分区：
文献类型：
--
作者：
Gangishetti U;Ramirez-Perez S;Jones K;Arif A;Drissi H;Bhattaram P
成纤维细胞样滑膜细胞（FLS）在类风湿关节炎（RA）的发病机制中起着关键作用。慢性炎症诱导转录组和表观遗传修饰，赋予FLS持久的分解代谢表型，尽管它们从炎症环境中解离。我们分析了来自人类和小鼠FLS的高通量基因表达和染色质可及性数据，这些数据来自我们和公共数据库上的其他研究，目的是识别慢性炎症驱动的持续重编程信号通路。我们发现，短期肿瘤坏死因子-α（TNF）治疗诱导的基因表达变化在暴露于慢性炎症的FLS中很大程度上是持续的。这些变化包括基因表达的激活和抑制，伴随着染色质可及性的重塑。持续活化基因（SAG）包括已知在NF-κ B、STAT和AP-1信号级联的多个水平起作用的已建立的促炎信号传导组分。有趣的是，持续抑制基因（SRG）包括BMP信号通路的关键介质和靶标。因此，我们确定持续抑制BMP信号作为一个独特的组成部分，长期炎症记忆诱导的慢性炎症。我们假设，同时针对这些激活和抑制的信号通路可能是必要的，以打击RA的持久性。
Fibroblast-like synoviocytes (FLS) play a critical role in the pathogenesis of rheumatoid arthritis (RA). Chronic inflammation induces transcriptomic and epigenetic modifications that imparts a persistent catabolic phenotype to the FLS, despite their dissociation from the inflammatory environment. We analyzed high throughput gene expression and chromatin accessibility data from human and mouse FLS from our and other studies available on public repositories, with the goal of identifying the persistently reprogrammed signaling pathways driven by chronic inflammation. We found that the gene expression changes induced by short-term tumor necrosis factor-alpha (TNF) treatment were largely sustained in the FLS exposed to chronic inflammation. These changes that included both activation and repression of gene expression, were accompanied by the remodeling of chromatin accessibility. The sustained activated genes (SAGs) included established pro-inflammatory signaling components known to act at multiple levels of NF-kappaB, STAT and AP-1 signaling cascades. Interestingly, the sustained repressed genes (SRGs) included critical mediators and targets of the BMP signaling pathway. We thus identified sustained repression of BMP signaling as a unique constituent of the long-term inflammatory memory induced by chronic inflammation. We postulate that simultaneous targeting of these activated and repressed signaling pathways may be necessary to combat RA persistence.
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肿瘤坏死因子α诱导持续的信号传导，并在类风湿关节炎滑膜成纤维细胞中延长且不舒服的炎症反应。
影响因子：
--
作者：
Lee A;Qiao Y;Grigoriev G;Chen J;Park-Min KH;Park SH;Ivashkiv LB;Kalliolias GD
通讯作者：
Kalliolias GD
DOI：
10.1002/art.40386
发表时间：
2018-03
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Bhattaram P;Muschler G;Wixler V;Lefebvre V
通讯作者：
Lefebvre V
影响因子：
5.2
作者：
Jia, Youchao;Wang, Zhigang;Fu, Yan
通讯作者：
Fu, Yan
DOI：
10.1126/stke.2002.151.pe40
发表时间：
2002-09-24
期刊：
Science's STKE : signal transduction knowledge environment
影响因子：
--
作者：
Miyazono, Kohei;Miyazawa, Keiji
通讯作者：
Miyazawa, Keiji
影响因子：
13.3
作者：
Ai, Rizi;Whitaker, John W.;Boyle, David L.;Tak, Paul Peter;Gerlag, Danielle M.;Wang, Wei;Firestein, Gary S.
通讯作者：
Firestein, Gary S.