Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes
Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes
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DOI：
10.1038/s41467-019-11139-3
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发表时间：
2019-07-12
影响因子：
16.6
通讯作者：
Piehl, Fredrik
中科院分区：
文献类型：
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作者：
Carlstrom, Karl E.;Ewing, Ewoud;Piehl, Fredrik
富马酸二甲酯（DMF）是复发缓解型多发性硬化症（RRMS）的一线治疗药物。氧化还原主调节剂Nrf 2对于氧化还原平衡至关重要，是DMF的靶点，但其精确的治疗作用机制仍然难以捉摸。在这里，我们在前瞻性纵向RRMS患者队列中显示了DMF对循环单核细胞和T细胞的影响。DMF增加外周血中氧化异前列烷的水平。其他观察到的变化，包括甲基化组和转录组谱，发生在单核细胞之前的T细胞。重要的是，DMF后单核细胞计数和单核细胞ROS增加，并将具有有益治疗应答的患者与无应答者区分开来。ROS生成NOX3基因的单核苷酸多态性与DMF治疗反应相关。我们的数据涉及自身免疫性疾病及其治疗中单核细胞衍生的氧化过程，并将NOX 3遗传变异体、单核细胞计数和氧化还原状态确定为可能用于告知RRMS DMF治疗临床决策的参数。
Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.