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

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.