Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis
Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis
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DOI：
10.1136/annrheumdis-2020-218189
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发表时间：
2021-04-01
影响因子：
27.4
通讯作者：
Fujio, Keishi
中科院分区：
文献类型：
--
作者：
Tsuchiya, Haruka;Ota, Mineto;Fujio, Keishi
目的滑膜成纤维细胞（SF）是类风湿关节炎（RA）滑膜炎性病变的主要成分之一。我们的目的是通过阐明炎症状态下SFs对分子调控网络的遗传贡献来深入了解SFs的致病机制。（每种n=30）用八种不同的细胞因子刺激（干扰素（IFN）-α，IFN-γ，肿瘤坏死因子-α，白细胞介素（IL）-1 β，IL-6/sIL-6 R，IL-17，转化生长因子-β 1，IL-18）或所有8种的组合（8种混合物）。将外周血单个核细胞分成5个免疫细胞亚群（CD 4（+）T细胞、CD 8（+）T细胞、B细胞、自然杀伤（NK）细胞、单核细胞）。结果未受刺激的RASFs与OASFs在转录组和表观基因组上存在显著差异。同时，对刺激的大部分反应在疾病之间是共享的。活化的SF表达致病基因，包括CD 40，其通过IFN-γ的诱导受到RA风险SNP（rs6074022）的显著影响。在激活的SF中的染色质重塑上，RA风险位点富集在协同促炎细胞因子诱导的增强子（超级增强子; SE）簇中。RA的风险SNP（rs 28411362），位于协同作用的细胞因子下的SE，形成3D接触的金属调节转录因子1（MTF 1）基因的启动子，其结合基序显示出显着富集的刺激特异性SE。一致，抑制MTF 1抑制细胞因子和趋化因子的生产从SF和改善小鼠模型arthritis.Conclusions我们的研究结果建立了动态景观激活SF和产生潜在的治疗目标与RA的遗传风险。
Objectives Synovial fibroblasts (SFs) are one of the major components of the inflamed synovium in rheumatoid arthritis (RA). We aimed to gain insight into the pathogenic mechanisms of SFs through elucidating the genetic contribution to molecular regulatory networks under inflammatory condition.Methods SFs from RA and osteoarthritis (OA) patients (n=30 each) were stimulated with eight different cytokines (interferon (IFN)-alpha, IFN-gamma, tumour necrosis factor-alpha, interleukin (IL)-1 beta, IL-6/sIL-6R, IL-17, transforming growth factor-beta 1, IL-18) or a combination of all 8 (8-mix). Peripheral blood mononuclear cells were fractioned into five immune cell subsets (CD4(+) T cells, CD8(+) T cells, B cells, natural killer (NK) cells, monocytes). Integrative analyses including mRNA expression, histone modifications (H3K27ac, H3K4me1, H3K4me3), three-dimensional (3D) genome architecture and genetic variations of single nucleotide polymorphisms (SNPs) were performed.Results Unstimulated RASFs differed markedly from OASFs in the transcriptome and epigenome. Meanwhile, most of the responses to stimulations were shared between the diseases. Activated SFs expressed pathogenic genes, including CD40 whose induction by IFN-gamma was significantly affected by an RA risk SNP (rs6074022). On chromatin remodelling in activated SFs, RA risk loci were enriched in clusters of enhancers (super-enhancers; SEs) induced by synergistic proinflammatory cytokines. An RA risk SNP (rs28411362), located in an SE under synergistically acting cytokines, formed 3D contact with the promoter of metal-regulatory transcription factor-1 (MTF1) gene, whose binding motif showed significant enrichment in stimulation specific-SEs. Consistently, inhibition of MTF1 suppressed cytokine and chemokine production from SFs and ameliorated mice model of arthritis.Conclusions Our findings established the dynamic landscape of activated SFs and yielded potential therapeutic targets associated with genetic risk of RA.