Abstract
Dimethyl fumarate (DMF) is an oral agent for relapsing-remitting multiple sclerosis (RRMS). In this study, we investigated the therapeutic mechanism of DMF using experimental autoimmune encephalomyelitis (EAE). DMF treatment decreased the proliferation of T cells and the production of IL-17A and GM-CSF. DMF treatment also decreased the development and/or infiltration of macrophages in the central nervous system (CNS), and reduced the ratio of iNOS+ pro-inflammatory macrophage versus Ym1+ immunomodulatory macrophages. Furthermore, DMF treatment suppressed the deposition of complement C3 (C3) and development of reactive C3+ astrocytes. The decrease in iNOS+ macrophages, C3+astrocytes, and C3 deposition in the CNS resulted in the reduction in demyelination and axonal loss. This study suggests that the beneficial effects of DMF involve the suppression of iNOS+ pro-inflammatory macrophages, C3+ astrocytes, and deposition of C3 in the CNS.
Highlights
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS)
We investigated the effect of dimethyl fumarate (DMF) treatment on the proliferation of T cells in the spleen and mesenteric lymph node (MLN)
Pro-inflammatory cytokines such as IFN-γ, IL-17A, and GM-CSF play critical roles in the initiation and progression of EAE, while IL-10 produced by regulatory T cells and innate immune cells plays a pivotal role in disease suppression [22]
Summary
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). Among the FDA-approved disease modifying agents for relapsing-remitting multiple sclerosis (RRMS), dimethyl fumarate (DMF) is an oral drug with neuroprotective and immunomodulatory effects [3,4,5]. DMF confers neuroprotection during neuroinflammation through the induction of the Nrf anti-oxidative pathway in glial cells and neurons [6]. Recent studies showed that anti-inflammatory effects of DMF are observed in a wide range of immune cells, including B cells, natural killer (NK) cells, T cells, dendritic cells (DCs) and macrophages through multiple targets such as hydroxycarboxylic acid receptor 2 (HCA2), interleukin-1 receptor-associated kinase 4 (IRAK4), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [9,10,11,12]. DMF can suppress the development of pathogenic immune cells in the periphery, migration of pathogenic immune cells into the CNS, and induction of neuroinflammation through several different pathways
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