Aberrant expression of USF2 in refractory rheumatoid arthritis and its regulation of proinflammatory cytokines in Th17 cells.
Aberrant expression of USF2 in refractory rheumatoid arthritis and its regulation of proinflammatory cytokines in Th17 cells.
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DOI：
10.1073/pnas.2007935117
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发表时间：
2020-12-01
影响因子：
11.1
通讯作者：
Weiner HL
中科院分区：
文献类型：
--
作者：
Hu D;Tjon EC;Andersson KM;Molica GM;Pham MC;Healy B;Murugaiyan G;Pochet N;Kuchroo VK;Bokarewa MI;Weiner HL
识别有助于类风湿关节炎对抗TNF治疗耐药的信号通路对于开发难治性类风湿关节炎的新治疗策略至关重要。Th 17细胞是促炎性CD 4 + T细胞的一个亚群，与疾病的发病机制有关。我们分析了抗TNF治疗的类风湿关节炎患者中Th 17富集的CD 4 + T细胞的基因表达谱，发现抗TNF难治性患者中转录因子USF 2的表达水平升高与Th 17细胞的促炎信号传导增加相关。在Th 17细胞中的USF 2敲低实验揭示USF 2促进Th 17细胞的致病性。这些发现对难治性类风湿性关节炎的新治疗策略的发展具有重要意义。产生IL-17的Th 17细胞与类风湿关节炎（RA）的发病机制有关，而类风湿关节炎中的促炎细胞因子TNF-α促进Th 17分化。抗TNF治疗可改善许多类风湿性关节炎（RA）患者的疾病。然而，很大一部分患者对这种疗法没有反应。抗TNF治疗对RA中Th 17应答的影响尚不清楚。我们对Th 17富集的CCR 6 + CXCR 3 − CD 45 RA − CD 4 + T（CCR 6 + T）细胞进行了高通量基因表达分析，这些细胞是从抗TNF治疗的RA患者中分离出来的，这些患者被分类为治疗应答者或非应答者。来自应答者和非应答者的CCR 6 + T细胞具有不同的基因表达谱。在无应答者的CCR 6 + T细胞中，促炎信号传导升高，并且在这些细胞中致病性Th 17特征基因上调。对这些特征基因的基因集富集分析确定转录因子USF 2为其上游调节因子，其在无应答者中也增加。重要的是，在致病性Th 17细胞中靶向USF 2的短发夹RNA导致促炎细胞因子IL-17 A、IFN-γ、IL-22和粒细胞-巨噬细胞集落刺激因子（GM-CSF）以及转录因子T-bet的表达减少。总之，我们的研究结果显示，在无应答者中，抗TNF对Th 17应答的抑制不足，直接靶向USF 2信号通路可能是抗TNF难治性RA的潜在治疗方法。
Identifying signaling pathways contributing to resistance to anti-TNF therapy in rheumatoid arthritis is crucial for the development of new therapeutic strategies for refractory rheumatoid arthritis. Th17 cells, a subset of proinflammatory CD4+ T cells, are implicated in the pathogenesis of the disease. We analyzed the gene expression profiles of Th17-enriched CD4+ T cells in anti-TNF–treated patients with rheumatoid arthritis and found that the elevated expression levels of transcription factor USF2 in anti-TNF refractory patients were associated with increased proinflammatory signaling of Th17 cells. USF2-knockdown experiments in Th17 cells revealed that USF2 promotes the pathogenicity of Th17 cells. These findings have implications for the development of new therapeutic strategies for refractory rheumatoid arthritis. IL-17–producing Th17 cells are implicated in the pathogenesis of rheumatoid arthritis (RA) and TNF-α, a proinflammatory cytokine in the rheumatoid joint, facilitates Th17 differentiation. Anti-TNF therapy ameliorates disease in many patients with rheumatoid arthritis (RA). However, a significant proportion of patients do not respond to this therapy. The impact of anti-TNF therapy on Th17 responses in RA is not well understood. We conducted high-throughput gene expression analysis of Th17-enriched CCR6+CXCR3−CD45RA− CD4+ T (CCR6+ T) cells isolated from anti-TNF–treated RA patients classified as responders or nonresponders to therapy. CCR6+ T cells from responders and nonresponders had distinct gene expression profiles. Proinflammatory signaling was elevated in the CCR6+ T cells of nonresponders, and pathogenic Th17 signature genes were up-regulated in these cells. Gene set enrichment analysis on these signature genes identified transcription factor USF2 as their upstream regulator, which was also increased in nonresponders. Importantly, short hairpin RNA targeting USF2 in pathogenic Th17 cells led to reduced expression of proinflammatory cytokines IL-17A, IFN-γ, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as well as transcription factor T-bet. Together, our results revealed inadequate suppression of Th17 responses by anti-TNF in nonresponders, and direct targeting of the USF2-signaling pathway may be a potential therapeutic approach in the anti-TNF refractory RA.
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影响因子：
2.8
作者：
Gabr, Mostafa A.;Jing, Liufang;Helbling, Antonia R.;Sinclair, S. Michael;Allen, Kyle D.;Shamji, Mohammed F.;Richardson, William J.;Fitch, Robert D.;Setton, Lori A.;Chen, Jun
通讯作者：
Chen, Jun
影响因子：
5.7
作者：
Andersson, Karin M. E.;Cavallini, Nicola Filluelo;Bokarewa, Maria I.
通讯作者：
Bokarewa, Maria I.
影响因子：
--
作者：
Cosmi, Lorenzo;Cimaz, Rolando;Annunziato, Francesco
通讯作者：
Annunziato, Francesco
影响因子：
27.4
作者：
Glatt, Sophie;Taylor, Peter C.;Shaw, Stevan
通讯作者：
Shaw, Stevan
影响因子：
3.7
作者：
Groom JR;Luster AD
通讯作者：
Luster AD