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

Karl E. Carlström, Ewoud Ewing, Mathias Granqvist, Alexandra Gyllenberg, Shahin Aeinehband, Sara Lind Enoksson, Antonio Checa, Tejaswi V.S. Badam, Jesse Huang, David Gomez-Cabrero, Mika Gustafsson, Faiez Al Nimer, Craig E. Wheelock, Ingrid Kockum, Tomas Olsson, Maja Jagodic, Fredrik Piehl

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

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.
Original languageEnglish (US)
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019
Externally publishedYes

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