Glatiramer acetate treatment negatively regulates type I interferon signaling
Glatiramer acetate treatment negatively regulates type I interferon signaling
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DOI：
10.1212/nxi.0000000000000179
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发表时间：
2015-12-01
影响因子：
8.8
通讯作者：
Zamvil, Scott S.
中科院分区：
文献类型：
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作者：
Molnarfi, Nicolas;Prod'homme, Thomas;Zamvil, Scott S.
目的：醋酸格拉替雷（GA; Copaxone），一种用于多发性硬化（MS）的疾病修饰疗法，促进可指导调节性T细胞分化的抗炎（M2，II型）单核细胞的发育。我们研究了天然免疫信号通路参与GA介导的M2单核细胞polarization.Methods：单核细胞分离自骨髓分化初级反应基因88（MyD 88）缺陷，Toll-IL-1受体域含有衔接诱导干扰素（IFN）-β（TRIF）缺陷，IFN-α/β受体亚单位1（IFNAR 1）缺陷，野生型（WT）小鼠和人外周血。用Toll样受体配体刺激GA处理的单核细胞，然后评估参与先天免疫的激酶和转录因子的激活以及促炎细胞因子的分泌。GA处理的小鼠进行了评价细胞因子分泌和易感性实验性自身免疫性脑脊髓炎。结果：GA介导的抑制单核细胞的促炎细胞因子的产生发生独立的MyD 88和核因子-kB，但被阻断TRIF缺乏症。此外，GA在TRIF缺陷小鼠中没有提供临床益处。GA抑制p38丝裂原活化蛋白激酶（ATF-2的上游调节因子）和c-Jun N-末端激酶1（调节IFN调节因子3（IRF 3））的活化。因此，ATF-2和IRF 3（IFN-β增强体的组分）的核转位受损。与这些观察结果一致，GA抑制WT小鼠体内IFN-β的产生，但不调节IFNAR 1缺陷小鼠单核细胞的促炎细胞因子产生。我们的结果表明GA抑制单核细胞M2极化中的I型IFN途径，与MyD 88无关，提供了在GA治疗中连接先天性和适应性免疫调节的重要机制以及关于其与其他MS治疗的潜在用途的有价值的见解。
Objective: Glatiramer acetate (GA; Copaxone), a disease-modifying therapy for multiple sclerosis (MS), promotes development of anti-inflammatory (M2, type II) monocytes that can direct differentiation of regulatory T cells. We investigated the innate immune signaling pathways that participate in GA-mediated M2 monocyte polarization.Methods: Monocytes were isolated from myeloid differentiation primary response gene 88 (MyD88)deficient, Toll-IL-1 receptor domain-containing adaptor inducing interferon (IFN)-beta (TRIF)-deficient, IFN-alpha/beta receptor subunit 1 (IFNAR1)-deficient, and wild-type (WT) mice and human peripheral blood. GA-treated monocytes were stimulated with Toll-like receptor ligands, then evaluated for activation of kinases and transcription factors involved in innate immunity, and secretion of proinflammatory cytokines. GA-treated mice were evaluated for cytokine secretion and susceptibility to experimental autoimmune encephalomyelitis.Results: GA-mediated inhibition of proinflammatory cytokine production by monocytes occurred independently of MyD88 and nuclear factor-kB, but was blocked by TRIF deficiency. Furthermore, GA did not provide clinical benefit in TRIF-deficient mice. GA inhibited activation of p38 mitogen-activated protein kinase, an upstream regulator of activating transcription factor (ATF)-2, and c-Jun N-terminal kinase 1, which regulates IFN regulatory factor 3 (IRF3). Consequently, nuclear translocation of ATF-2 and IRF3, components of the IFN-beta enhanceosome, was impaired. Consistent with these observations, GA inhibited production of IFN-beta in vivo in WT mice, but did not modulate proinflammatory cytokine production by monocytes from IFNAR1-deficient mice.Conclusion: Our results demonstrate that GA inhibits the type I IFN pathway in M2 polarization of monocytes independently of MyD88, providing an important mechanism connecting innate and adaptive immune modulation in GA therapy and valuable insight regarding its potential use with other MS treatments.