Regulation of Synovial Inflammation and Tissue Destruction by Guanylate Binding Protein 5 in Synovial Fibroblasts From Patients With Rheumatoid Arthritis and Rats With Adjuvant-Induced Arthritis.
Regulation of Synovial Inflammation and Tissue Destruction by Guanylate Binding Protein 5 in Synovial Fibroblasts From Patients With Rheumatoid Arthritis and Rats With Adjuvant-Induced Arthritis.
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风湿性关节炎患者和佐剂诱导关节炎大鼠滑膜成纤维细胞中鸟苷酸结合蛋白5对滑膜炎症和组织破坏的调节
DOI：
10.1002/art.41611
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发表时间：
2021-06
影响因子：
13.3
通讯作者：
Ahmed, Salahuddin
中科院分区：
文献类型：
--
作者：
Haque, Mahamudul;Singh, Anil K.;Ouseph, Madhu M.;Ahmed, Salahuddin
风湿性关节炎滑膜成纤维细胞（RASFs）是滑膜炎症和关节破坏的重要介质。然而，其在慢性炎症下的内在免疫调节机制仍不清楚。因此，本研究旨在了解新发现的鸟苷酸结合蛋白5（GBP-5）在RA发病机制中的作用。使用qRT-PCR在RA滑膜组织（RAST）或非患病ST（NLST）中评价GBP 1-GBP 7转录物的表达。在人RASF中的瞬时siRNA敲低和慢病毒过表达研究检查了GBP-5对促炎细胞因子信号传导途径的调节作用。无偏全转录组RNA测序分析检查了GBP-5对RASF分子功能的影响。这些发现证实了使用体内大鼠模型的佐剂诱导的关节炎（AIA）。在评估的不同GBP中，GBP-5在RAST（p<0.05; n=4）和AIA大鼠关节（p<0.05; n=6）中选择性上调，并且在人RASF中由IL-1β、TNF-α和/或IFN-γ显著诱导（p<0.05; n=3）。RNA测序数据的生物信息学分析鉴定了GBP-5改变的主要功能是精氨酸-细胞因子受体信号传导，而IL-6信号传导是主要靶点。GBP-5的敲低使IL-1β诱导的IL-6、IL-8、ENA-78/CXCL 5分别增加44%、54%、45%，MMP-1的产生增加数倍，而外源性GBP-5的作用逆转。GBP-5的缺乏增加了IFN-γ诱导的人RASF的增殖和迁移。使用关节内siRNA的体内GBP-5敲低加剧了AIA的疾病发作、严重程度、滑膜炎和骨破坏。GBP-5由RASF响应于细胞因子刺激而表达，具有恢复RA中细胞稳态和钝化炎症和组织破坏的潜力。
Rheumatoid arthritis synovial fibroblasts (RASFs) are crucial mediators of synovial inflammation and joint destruction. However, their intrinsic immunoregulatory mechanisms under chronic inflammation remain unclear. Thus, present study was aimed to understand the role of newly identified GTPase, guanylate-binding protein 5 (GBP-5) in RA pathogenesis. The expression of GBP1-GBP7 transcripts was evaluated using qRT-PCR in RA synovial tissues (RASTs) or non-diseased STs (NLSTs). Transient siRNA knockdown and lentiviral overexpression studies in human RASFs examined the regulatory role of GBP-5 on proinflammatory cytokine signaling pathways. Unbiased whole transcriptome RNA-sequencing analysis examined the impact of GBP-5 on RASF molecular functions. These findings were confirmed using in vivo rat model of adjuvant-induced arthritis (AIA). Among different GBPs evaluated, GBP-5 was selectively upregulated in RASTs (p<0.05; n=4) and the joints of AIA rats (p<0.05; n=6), and was significantly induced in human RASFs by IL-1β, TNF-α and/or IFN-γ (p<0.05; n=3). Bioinformatics analysis of RNA-sequencing data identified cytokine-cytokine receptor signaling as a major function altered by GBP-5, with IL-6 signaling as a primary target. Knockdown of GBP-5 amplified IL-1β-induced IL-6, IL-8, ENA-78/ CXCL5 by 44%, 54%, 45%, respectively, and MMP-1 production by several-folds, effects which reversed with exogenously delivered GBP-5. Lack of GBP-5 increased IFN-γ-induced proliferation and migration in human RASFs. In vivo GBP-5 knockdown using intra-articular siRNA exacerbated disease onset, severity, synovitis, and bone destruction in AIA. Expressed by RASFs in response to cytokine stimulation, GBP-5 has potential to restore cellular homeostasis and blunt inflammation and tissue destruction in RA.
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影响因子：
30.5
作者：
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通讯作者：
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影响因子：
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作者：
Fechtner, Sabrina;Singh, Anil K.;Ahmed, Salahuddin
通讯作者：
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