Abstract
Dimethylfumarate (DMF) has been approved the for treatment of relapsing-remitting multiple sclerosis. The mode of action of DMF and its assumed active primary metabolite monomethylfumarate (MMF) is still not fully understood, notably for brain resident cells. Therefore we investigated potential direct effects of DMF and MMF on microglia and indirect effects on oligodendrocytes. Primary rat microglia were differentiated into M1-like, M2-like and M0 phenotypes and treated in vitro with DMF or MMF. The gene expression of pro-inflammatory and anti-inflammatory factors such as growth factors (IGF-1), interleukins (IL-10, IL-1β), chemokines (CCl3, CXCL-10) as well as cytokines (TGF-1β, TNFα), iNOS, and the mannose receptor (MRC1) was examined by determining their transcription level with qPCR, and on the protein level by ELISA and FACS analysis. Furthermore, microglia function was determined by phagocytosis assays and indirect effects on oligodendroglial proliferation and differentiation. DMF treatment of M0 and M1-like polarized microglia demonstrated an upregulation of gene expression for IGF-1 and MRC1, but not on the protein level. While the phagocytic activity remained unchanged, DMF and MMF treated microglia supernatants led to an enhanced proliferation of oligodendrocyte precursor cells (OPC). These results suggest that DMF has anti-inflammatory effects on microglia which may result in enhanced proliferation of OPC.
Highlights
Multiple sclerosis (MS) is the most common chronic disease of the central nervous system (CNS) in young adults [1]
Phagocytosis is a hallmark of microglia and due to different effector molecules microglia are thought to be involved the in development of CNS lesions as well as in neuroprotection and remyelination [5,6]
As we demonstrated that insulin-like growth factor-1 (IGF-1) gene expression is upregulated in M0- and M1-like microglia treated with DMF, we performed further Enzyme-linked Immunosorbent Assay (ELISA) and FACS analysis of IGF-1 in rat microglia
Summary
Multiple sclerosis (MS) is the most common chronic disease of the central nervous system (CNS) in young adults [1]. During inflammation the cells are rapidly activated and several factors essential for remyelination are produced by microglia [10] One of these factors is insulin-like growth factor-1 (IGF-I), which has been demonstrated to have neurotrophic effects on neural tissue, notably promoting oligodendrocyte differentiation in vitro [11,12,13,14]. Several in vitro studies demonstrated that DMF has immune-modulatory properties on T cells by promoting their cytokine release profile towards anti-inflammatory Th2 cells rather than proinflammatory Th1 and Th17 cells [20,21], and might modulate microglia activation and their phenotype [22,23]. In order to elucidate the effects of DMF on microglia, we first analyzed modulatory influences of DMF and MMF on regulation of cytokines and growth factors in different microglial phenotypes in vitro and analyzed secondary effects of DMF and MMF on proliferation and differentiation of oligodendrocyte precursor cells
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