Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity

Abstract

Dimethyl fumarate, an approved treatment for relapsing-remitting multiple sclerosis, exerts pleiotropic effects on immune cells as well as CNS resident cells. Here, we show that dimethyl fumarate exerts a profound alteration of the metabolic profile of human CD4 + as well as CD8 + T cells and restricts their antioxidative capacities by decreasing intracellular levels of the reactive oxygen species scavenger glutathione. This causes an increase in mitochondrial reactive oxygen species levels accompanied by an enhanced mitochondrial stress response, ultimately leading to impaired mitochondrial function. Enhanced mitochondrial reactive oxygen species levels not only result in enhanced T-cell apoptosis in vitro as well as in dimethyl fumarate-treated patients, but are key for the well-known immunomodulatory effects of dimethyl fumarate both in vitro and in an animal model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis. Indeed, dimethyl fumarate immune-modulatory effects on T cells were completely abrogated by pharmacological interference of mitochondrial reactive oxygen species production. These data shed new light on dimethyl fumarate as bona fide immune-metabolic drug that targets the intracellular stress response in activated T cells, thereby restricting mitochondrial function and energetic capacity, providing novel insight into the role of oxidative stress in modulating cellular immune responses and T cell-mediated autoimmunity.

GFI1B acts as a metabolic regulator in hematopoiesis and acute myeloid leukemia

“…Seahorse Extracellular Flux analysis was performed according to the manufacturer’s protocol as described [ 18 , 19 ]. Briefly, cells in appropriate numbers were seeded in Poly-D-Lysine (Sigma-Aldrich, Darmstadt, Germany) coated XFe96 plates (Agilent Technologies, North Billerica, MA, USA) in the XF DMEM medium with optimized concentrations of supplements.…”

Redox signaling at the crossroads of human health and disease

“…Nrf2 activators have been extensively applied in clinical research, among which sulforaphane, synthetic triterpenoids, and dimethyl fumarate are the most successful examples. 184 , 411 In preclinical studies, these three compounds were widely reported to function in many disease situations including type 2 diabetes, 425 epilepsy, 426 pachyonychia congenita, 427 cancers, 428 , 429 , 430 autoimmunity, 431 AD, 432 and infections. 433 A large number of clinical trials are currently being carried out in patients with a range of disorders, some of which have undergone preliminary tests and some have even been approved (NCT01335971, NCT03517995, NCT00322140, NCT02683863).…”

Gut microbiota composition as a candidate risk factor for dimethyl fumarate-induced lymphopenia in multiple sclerosis

“…In this context, recent publications 2–6 set a spotlight on dimethyl fumarate (DMF), a frequently administered DMT. DMF is a bona fide immunometabolic compound with metabolic properties on the mitochondrial respiration of activated T cells 5 and restrictive effects on glycolysis in lymphocytes. 2 , 6 Yet, it is likely that the effects of this empirically developed, untargeted, small molecule reach beyond T cells, potentially affecting other metabolically active human and bacterial cells.…”