Nrf2 and beyond: deciphering the mode of action of fumarates in the inflamed central nervous system.

Abstract

observed in degenerating cells with considerable differences in expression patterns depending on cell type. This detailed description of cellular expression patterns (and sources) of Nrf2 in different CNS regions of pathological brain specimens is relevant since it (re)emphasizes that oxidative stress seems to be an important pathomechanism of demyelination and neurodegeneration in MS. It further supports the view that therapeutic targeting of the Nrf2 pathway might indeed be a reasonable strategy in preventing oligodendrocyte degeneration. Notably, Nrf2 expression differed considerably between neural and glial cell types: immunoreactivity against Nrf2 was only rarely detectable in neurons. It might therefore be tempting to speculate that a potential protective role of DMF against oxidative stress might be more effective in active white matter lesions as compared to grey matter. This work using human materials provides important insight into “real” disease not obtainable using experimental models, while conclusions on DMF drug effects or even more general—on the role of Nrf2 in the dynamics of lesion evolution versus resolution—naturally remain difficult. In the second publication, Uccelli and co-workers report that MMF (the biochemical derivate of DMF after metabolization in vivo) can switch the functional phenotype of activated microglia from a pro-inflammatory type to an (indirect) anti-inflammatory (or “neuroprotective”) type [8]. Interestingly, this effect was mediated through activation of the hydroxycarboxylic acid receptor 2 (HCAR2), a G protein-coupled membrane receptor. This receptor has already been reported to be critically involved in therapeutic efficacy of DMF in preclinical EAE studies, its specific role, however, remained elusive at that stage [1]. In the present article, the authors demonstrate that LPS-activated microglia express HCAR2 and that binding of MMF to this receptor in vitro activates a downstream pathway mediated Dimethyl fumarate (DMF) is an oral drug based on recent phase III studies that has been approved by the US Food and Drug Administration and European Medicines Agency for the treatment of relapsing forms of multiple sclerosis (MS) [2, 4]. Its mode of action, however, still remains elusive. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, DMF demonstrated immunomodulatory as well as neuroprotective effects translating into disease amelioration and clinical improvement [7, 9]. DMF is rapidly metabolized to monomethyl fumarate (MMF), both of which covalently modify glutathione and KEAP-1, the inhibitor of the antioxidant transcription factor nuclear factor erythroid-derived 2–related factor 2 (Nrf2), and induce hemoxygenase-1 (HMOX1), NADP(H) quinoline oxidoreductase-1 (NQO1), and other genes [3, 7]. Whether the covalent modifications occur in vivo and eventually translate in attenuation of MS pathology is still unclear [1]. However, one key hypothesis for the therapeutic efficacy of DMF is its action through a Nrf2-dependent anti-oxidative pathway [5]. In the present issue of Acta Neuropathologica, two publications provide further evidence for Nrf2 as a relevant therapeutic target in MS: In the first article, Licht-Mayer and colleagues report positive immunoreactivity against Nrf2 in active MS lesions from formalin-fixed autopsy brain tissue [6]. Nrf2 was particularly localized to mature oligodendrocytes and most extensive expression was