Dimethyl fumarate downregulates the immune response through the HCA2/GPR109A pathway: Implications for the treatment of multiple sclerosis

Felipe von Glehn; Rafael P C Dias-Carneiro; Adriel S Moraes; Alessandro S Farias; Veronica A P G Silva; Francisco T M Oliveira; Carlos Eduardo B G Silva; Fabricio de Carvalho; Elaine Rahal; Clare Baecher-Allan; Leonilda M B Santos

doi:10.1016/j.msard.2018.04.016

Dimethyl fumarate downregulates the immune response through the HCA₂/GPR109A pathway: Implications for the treatment of multiple sclerosis

Mult Scler Relat Disord. 2018 Jul:23:46-50. doi: 10.1016/j.msard.2018.04.016. Epub 2018 Apr 25.

Affiliations

¹ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, USA; Neuroimmunology Unit, Department of Genetics, Evolution and Bioagents, Institute of Biology; University of Campinas, Campinas, Brazil. Electronic address: felipeglehn@gmail.com.
² Neuroimmunology Unit, Department of Genetics, Evolution and Bioagents, Institute of Biology; University of Campinas, Campinas, Brazil; CATEM- Center for Multiple Sclerosis Care, Santa Casa de São Paulo, São Paulo, Brazil.. Electronic address: r.paterno@me.com.
³ Neuroimmunology Unit, Department of Genetics, Evolution and Bioagents, Institute of Biology; University of Campinas, Campinas, Brazil. Electronic address: moraesadr@yahoo.com.br.
⁴ Neuroimmunology Unit, Department of Genetics, Evolution and Bioagents, Institute of Biology; University of Campinas, Campinas, Brazil; National Institute for Science and Technology - Neuroimmunomodulation (INCT-NIM), CNPq, Brazil. Electronic address: farias.as@gmail.com.
⁵ Neuroimmunology Unit, Department of Genetics, Evolution and Bioagents, Institute of Biology; University of Campinas, Campinas, Brazil. Electronic address: veronicaalmeida1@yahoo.com.br.
⁶ Neuroimmunology Unit, Department of Genetics, Evolution and Bioagents, Institute of Biology; University of Campinas, Campinas, Brazil; CATEM- Center for Multiple Sclerosis Care, Santa Casa de São Paulo, São Paulo, Brazil.. Electronic address: towmaz@gmail.com.
⁷ Biogen, São Paulo, SP, Brazil. Electronic address: carlos.dasilva@biogen.com.
⁸ Biogen, São Paulo, SP, Brazil. Electronic address: fabricio.carvalho.phd@gmail.com.
⁹ Biogen, São Paulo, SP, Brazil. Electronic address: elaine.rahal@biogen.com.
¹⁰ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, USA. Electronic address: callan@rics.bwh.harvard.edu.
¹¹ Neuroimmunology Unit, Department of Genetics, Evolution and Bioagents, Institute of Biology; University of Campinas, Campinas, Brazil; National Institute for Science and Technology - Neuroimmunomodulation (INCT-NIM), CNPq, Brazil. Electronic address: leonilda@unicamp.br.

PMID: 29763776
DOI: 10.1016/j.msard.2018.04.016

Abstract

Background: The mechanisms of action of dimethyl fumarate (DMF), and its metabolite, monomethyl fumarate (MMF), for the treatment of multiple sclerosis are not completely elucidated.

Objectives: To discuss the role of DMF/MMF-induced hydroxycarboxylic acid receptor 2 (HCA₂/GPR109A) pathway activation in the immune response and treatment of MS.

Methods: A narrative (traditional) review of the current literature.

Results: Studies have shown that binding of DMF/MMF to HCA₂ on dendritic cells inhibits the production of pro-inflammatory cytokines in vitro and in MS murine models. Evidence suggests that activation of HCA₂ expressed in immune cells and gut epithelial cells by DMF/MMF, may induce anti-inflammatory responses in the intestinal mucosa.

Conclusion: Although the DMF/MMF mechanism of action remains unclear, evidence suggests that the activation of HCA₂/GPR109A pathway downregulates the immune response and may activate anti-inflammatory response in the intestinal mucosa, possibly leading to reduction in CNS tissue damage in MS patients.

Keywords: Dimethyl fumarate; Hydroxycarboxylic acid receptor 2; Monomethyl fumarate; Multiple sclerosis.

Publication types

Review

MeSH terms

Animals
Dimethyl Fumarate / therapeutic use*
Humans
Immunosuppressive Agents / therapeutic use*
Multiple Sclerosis / drug therapy*
Multiple Sclerosis / immunology*
Receptors, G-Protein-Coupled / metabolism*
Receptors, Nicotinic / metabolism*
Signal Transduction / drug effects

Substances

Immunosuppressive Agents
Receptors, G-Protein-Coupled
Receptors, Nicotinic
Dimethyl Fumarate