风湿

甲氨蝶呤可通过A20依赖的交叉耐受机制限制炎症

作者:翻译者:冯媛,西京医院临床免疫科 来源:西京风湿免疫 日期:2018-05-09
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         甲氨蝶呤可通过A20依赖的交叉耐受机制限制炎症

关键字:  甲氨蝶呤 

        目标:

        甲氨蝶呤(MTX)是治疗类风湿性关节炎(RA)的主要药物,但其抗炎作用机制尚不完全清楚。在RA中,巨噬细胞呈现出明显的促炎作用,类似经GM-CSF分化的巨噬细胞。巨噬细胞对MTX的应答也只见于胸苷酸合成酶阳性的GM-CSF依赖的巨噬细胞。为了确定MTX抗炎作用的分子基础,作者探讨了GM-CSF活化的巨噬细胞中MTX与Toll样受体(TLR),RA滑膜液(RASF)和肿瘤坏死因子受体(TNFR)等信号通路间的作用。

        方法:

        通过实时定量PCR、免疫印迹、ELISA和siRNA敲除的方法测定TLR配体、TNFα或RASF作用于小剂量MTX孵育的巨噬细胞的相关作用。甲氨蝶呤的体内的作用通过对甲氨蝶呤单药治疗关节炎患者和小鼠败血症模型进行了评估。

        结果:

        MTX将巨噬细胞限制于一种近似免疫耐受的状态,它可以减少LPS、LTA、TNFα或RASF刺激后巨噬细胞产生白细胞介素(IL)-6和IL-1β。MTX可抑制LPS诱导的MAPK和NF-κB的激活和TRIF1依赖的信号通路。相反,MTX可增加NF-κB抑制物A20(TNFAIP3)的表达。A20本身还是RA的易感基因。MTX诱导的巨噬细胞耐受依赖于A20的表达,而siRNA介导的A20表达减少可逆转MTX诱导的IL-6表达降低。在体内研究中,经MTX单药治疗的RA患者PBMC中TNFAIP3的表达量显著升高,且经MTX治疗的小鼠也表现对LPS刺激后炎症反应的减少。

        结论:

        MTX通过上调A20的表达来抑制巨噬细胞的炎症反应。MTX可通过诱导A20介导的先天耐受机制而限制RA滑膜中的炎症,且A20可作为一个潜在的MTX应答生物标志物。

        参考文献:Methotrexate limits inflammation through an A20-dependentcross-tolerance mechanism.

        Ann Rheum Dis.2018 Feb 3.

        Abstract:

        OBJECTIVES:Methotrexate (MTX) is the anchor drug for treatment of rheumatoid arthritis(RA), but the mechanism of its anti-inflammatory action is not fullyunderstood. In RA, macrophages display a proinflammatory polarisation profilethat resemblesgranulocyte-macrophage colony-stimulating factor(GM-CSF)-differentiated macrophages and the response to MTX is only observed inthymidylate synthase+GM-CSF-dependentmacrophages. To determine the molecular basis for the MTX anti-inflammatoryaction, we explored toll-like receptor (TLR), RA synovial fluid (RASF) andtumour necrosis factor receptor (TNFR)-initiated signalling in MTX-exposedGM-CSF-primed macrophages.

        METHODS:Intracellular responses to TLR ligands, TNFα or RASF stimulation in long-termlow-dose MTX-exposed human macrophages were determined through quantitativereal-time PCR, western blot, ELISA and siRNA-mediated knockdown approaches. Therole of MTX in vivo was assessed in patients with arthritis under MTXmonotherapy and in a murine sepsis model.

        RESULTS:MTX conditioned macrophages towards a tolerant state, diminishing interleukin(IL)-6 and IL-1β production in LPS, LTA, TNFα or RASF-challenged macrophages.MTX attenuated LPS-induced MAPK and NF-κB activation, and toll/IL-1Rdomain-containing adaptor inducing IFN-beta (TRIF1)-dependent signalling.Conversely, MTX increased the expression of the NF-κB suppressor A20 (TNFAIP3),itself a RA-susceptibility gene. Mechanistically, MTX-induced macrophagetolerance was dependent on A20, as siRNA-mediated knockdown of A20 reversed theMTX-induced reduction of IL-6 expression. In vivo,TNFAIP3expression wassignificantly higher in peripheral blood cells of MTX-responsive individualsfrom a cohort of patients with arthritis under MTX monotherapy, whereasMTX-treated miceexhibited reduced inflammatory responses to LPS.

        CONCLUSIONS: MTX impairs macrophageproinflammatory responses through upregulation of A20 expression. TheA20-mediated MTX-induced innate tolerance might limit inflammation in the RAsynovial context, and positions A20 as a potential MTX-response biomarker.

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