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Nat Commun. 2019 Jul 12;10(1):3081. doi: 10.1038/s41467-019-11139-3.

Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes.

Author information

1
Department of Clinical Neurosciences, Section of Neurology, Karolinska Institutet, Stockholm, Sweden. karl.carlstrom@ki.se.
2
Department of Clinical Neurosciences, Section of Neurology, Karolinska Institutet, Stockholm, Sweden.
3
Department of Clinical Immunology Karolinska University Hospital, Stockholm, Sweden.
4
Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
5
Department of Bioinformatics, School of Bioscience, University of Skövde, Skövde, Sweden.
6
Department of Physics, Chemistry & Biology (IFM), Bioinformatics, Linköping University, Linköping, Sweden.
7
Translational Bioinformatics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Publica de Nevarra (UPNA), IdiSNA, Pamplona, Spain.
8
Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.

Abstract

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.

PMID:
31300673
PMCID:
PMC6626021
DOI:
10.1038/s41467-019-11139-3
[Indexed for MEDLINE]
Free PMC Article

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