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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 3081 (07 12 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 31300673 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Reactive Oxygen Species
• NADPH Oxidases
• Nox3 protein, human
• Dimethyl Fumarate

Topics

• Adult
• DNA Methylation (drug effects)
• Dimethyl Fumarate (pharmacology, therapeutic use)
• Epigenesis, Genetic (drug effects)
• Female
• Humans
• Immunosuppressive Agents (pharmacology, therapeutic use)
• Leukocyte Count
• Longitudinal Studies
• Male
• Middle Aged
• Monocytes (immunology, metabolism)
• Multiple Sclerosis, Relapsing-Remitting (blood, drug therapy, immunology)
• NADPH Oxidases (genetics, metabolism)
• NF-E2-Related Factor 2 (antagonists & inhibitors, metabolism)
• Polymorphism, Single Nucleotide
• Prospective Studies
• Reactive Oxygen Species (metabolism)
• T-Lymphocytes (immunology, metabolism)
• Treatment Outcome