The NRF2 pathway as potential biomarker for dimethyl fumarate treatment in multiple sclerosis

Hammer A, Waschbisch A, Kuhbandner K, Bayas A, Lee DH, Duscha A, Haghikia A, Gold R, Linker R (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Annals of Clinical and Translational Neurology Wiley

Book Volume: 5

Pages Range: 668-676

Journal Issue: 6

DOI: 10.1002/acn3.553

Abstract

Objective: Immunological studies have demonstrated a plethora of beneficial effects of dimethyl fumarate (DMF) on various cell types. However, the cellular and molecular targets are incompletely understood and response markers are scarce. Here, we focus on the relation between nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway induction under DMF therapy and the composition of the blood immune cell compartment and clinical efficacy in relapsing-remitting multiple sclerosis (MS) patients. Methods: We explored effects of DMF on peripheral immune cell subsets by flow cytometric and transcriptional analysis of serial blood samples obtained from 43 MS patients during the first year of therapy. Results: Gene expression analysis proved activation of NRF2 signaling under DMF therapy that was paralleled by a temporal expansion of FoxP3+ regulatory T cells, CD56bright natural killer cells, plasmacytoid dendritic cells, and a decrease in CD8+ T cells, B cells, and type 1 myeloid dendritic cells. In a subgroup of 28 patients with completely available clinical data, individuals with higher levels of the NRF2 target gene NAD(P)H quinone dehydrogenase 1 (NQO1) 4-6 weeks after DMF therapy initiation were more likely to achieve no evidence of disease activity status 1 year later. The degree of NQO1 induction further correlated with patient age. Interpretation: We demonstrate that positive effects of DMF on the clinical outcome are paralleled by induction of the antioxidant NRF2 transcriptional pathway and a shift toward regulatory immune cell subsets in the periphery. Our data identify a role of the NRF2 pathway as potential biomarker for DMF treatment in MS.

Authors with CRIS profile

Anne Waschbisch Medizinische Fakultät Kristina Kuhbandner Department of Neurology De-Hyung Lee Medizinische Fakultät Ralf Linker Department of Neurology

Involved external institutions

Ruhr-Universität Bochum (RUB) DE Germany (DE) Universitätsklinikum Augsburg DE Germany (DE)

How to cite

APA:

Hammer, A., Waschbisch, A., Kuhbandner, K., Bayas, A., Lee, D.-H., Duscha, A.,... Linker, R. (2018). The NRF2 pathway as potential biomarker for dimethyl fumarate treatment in multiple sclerosis. Annals of Clinical and Translational Neurology, 5(6), 668-676. https://doi.org/10.1002/acn3.553

MLA:

Hammer, Anna, et al. "The NRF2 pathway as potential biomarker for dimethyl fumarate treatment in multiple sclerosis." Annals of Clinical and Translational Neurology 5.6 (2018): 668-676.

BibTeX: Download