TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis
TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis
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DOI：
10.1016/j.jaut.2018.01.004
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发表时间：
2018-06-01
影响因子：
12.8
通讯作者：
Cunha, Fernando Q.
中科院分区：
文献类型：
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作者：
Peres, Raphael S.;Donate, Paula B.;Cunha, Fernando Q.
类风湿性关节炎（RA）是一种以慢性关节炎症为特征的自身免疫性关节病。甲氨蝶呤 (MTX) 仍然是 RA 的一线治疗药物，其抗炎作用与维持高水平的细胞外腺苷 (ADO) 相关。尽管如此，高达 40% 的 RA 患者对 MTX 治疗有耐药性，这与循环调节性 T 细胞 (Treg) 上 CD39 表达的减少有关，CD39 是一种参与 ATP 代谢产生细胞外 ADO 的胞外酶。然而，介导 Tregs 上 CD39 表达减少的机制尚不清楚。在这里，我们证明 TGF-β 信号传导受损会导致 Tregs 上 CD39 表达的减少，从而导致 MTX 耐药。 TGF-β 通过激活 TGFBRII/TGFBRI、SMAD2 和转录因子 CREB 来增加 Tregs 上的 CD39 表达，CREB 以 p38 依赖性方式激活，并通过促进 ENTPDI 基因转录来诱导 CD39 表达。重要的是，与 MTX 有反应的患者 (R-MTX) 相比，对 MTX 无反应的患者 (UR-MTX) 显示 Tregs 中 TGFBR2 和 CREBI 的表达降低，以及 p-SMAD2 和 p-CREB 水平降低。此外，携带至少一个 TGFBR2 基因 rs1431131（AT 或 AA）突变等位基因的 RA 患者与 UR-MTX 显着相关（p = 0.0006）。因此，我们发现了 Tregs 上 CD39 表达减少的分子机制，并揭示了 MTX 耐药治疗干预的潜在靶点。 (C) 2018 Elsevier Ltd. 保留所有权利。
Rheumatoid arthritis (RA) is an autoimmune arthropathy characterized by chronic articular inflammation. Methotrexate (MTX) remains the first-line therapy for RA and its anti-inflammatory effect is associated with the maintenance of high levels of extracellular adenosine (ADO). Nonetheless, up to 40% of RA patients are resistant to MTX treatment and this is linked to a reduction of CD39 expression, an ectoenzyme involved in the generation of extracellular ADO by ATP metabolism, on circulating regulatory T cells (Tregs). However, the mechanism mediating the reduction of CD39 expression on Tregs is unknown. Here we demonstrated that the impairment in TGF-beta signalling lead to the reduction of CD39 expression on Tregs that accounts for MTX resistance. TGF-beta increases CD39 expression on Tregs via the activation of TGFBRII/TGFBRI, SMAD2 and the transcription factor CREB, which is activated in a p38-dependent manner and induces CD39 expression by promoting ENTPDI gene transcription. Importantly, unresponsive patients to MTX (UR-MTX) show reduced expression of TGFBR2 and CREBI and decreased levels of p-SMAD2 and p-CREB in Tregs compared to MTX-responsive patients (R-MTX). Furthermore, RA patients carrying at least one mutant allele for rs1431131 (AT or AA) of the TGFBR2 gene are significantly (p = 0.0006) associated with UR-MTX. Therefore, we have uncovered a molecular mechanism for the reduced CD39 expression on Tregs, and revealed potential targets for therapeutic intervention for MTX resistance. (C) 2018 Elsevier Ltd. All rights reserved.