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

Abstract

ObjectiveImmunological 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.MethodsWe 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.ResultsGene 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.InterpretationWe 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.

Targeting immunometabolism as an anti-inflammatory strategy

“…8 In addition, analyzing subsets of peripheral immune cell subsets from MS patients undergoing DMF therapy revealed an expansion of FoxP3 + regulatory T cells, CD56bright NK cells and plasmacytoid dendritic cells accompanied by a decrease in CD8 + T cells, B cells and type 1 myeloid dendritic cells. 9 Limiting peripheral autoreactive T cell counts following treatment with DMF was a phenomenon first identified in psoriasis patients, but has also been reported in MS patients. 10 This drop in primarily CD8 + , but also to a lesser extent CD4 + T cell numbers, is caused by an increased induction of apoptosis and a reduced rate of proliferation.…”

Dimethyl fumarate, a two‐edged drug: Current status and future directions

“…As mentioned above, DMF mediates its immunoregulatory effects through the regulation of GSH content/ROS production, and the downregulation of NF‐κB. A recent study reported that the positive effects of DMF on the clinical outcome of MS (ie, no evidence of disease activity) correlated with higher levels of NRF2 target genes (NQO 1 induction) in several immune cell populations …”

“…A recent study reported that the positive effects of DMF on the clinical outcome of MS (ie, no evidence of disease activity) correlated with higher levels of NRF2 target genes (NQO 1 induction) in several immune cell populations. 62…”

Regulation of leukocyte function by citric acid cycle intermediates

“…A clinical study by Hammer et al. involving MS patients, showed that DMF treatment activated the Nrf2 transcriptional pathway and facilitated a shift toward regulatory immune cell subsets . Treatment with DMF has been shown to be protective in a mouse model of cardiac ischemia‐reperfusion (IR) injury via Nrf2‐dependent up‐regulation of antioxidant target genes and it was not associated with HIF‐1α stabilization .…”