Dimethyl Fumarate Suppresses Demyelination and Axonal Loss through Reduction in Pro-Inflammatory Macrophage-Induced Reactive Astrocytes and Complement C3 Deposition

Sudhir K Yadav; Naoko Ito; Devika Soin; Kouichi Ito; Suhayl Dhib-Jalbut

doi:10.3390/jcm10040857

Dimethyl Fumarate Suppresses Demyelination and Axonal Loss through Reduction in Pro-Inflammatory Macrophage-Induced Reactive Astrocytes and Complement C3 Deposition

J Clin Med. 2021 Feb 19;10(4):857. doi: 10.3390/jcm10040857.

Authors

Sudhir K Yadav¹, Naoko Ito¹, Devika Soin^{1

2}, Kouichi Ito¹, Suhayl Dhib-Jalbut^{1

3}

Affiliations

¹ Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
² Touro College of Osteopathic Medicine, Middletown, NY 10940, USA.
³ Department of Neurology, New Jersey Medical School, Newark, NJ 07101, USA.

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.

Keywords: Ym1+ macrophages; axonal loss; complement C3; demyelination; dimethyl fumarate; experimental autoimmune encephalomyelitis; iNOS+ macrophage; immunomodulatory; multiple sclerosis; neuroprotection; proinflammatory; reactive C3+ astrocytes.

Grants and funding

US-BGT-14-10690/Biogen Idec