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

•DMF may act in neurodegeneration and inflammation by activating the Nrf2 pathway.•DMF and MMF downregulates the immune response through HCA2/GPR109A pathway.•Nrf2 and HCA2/GPR109A pathways activation may explain DMF's efficacy and safety profile. The mechanisms of action of dimethyl fumarate (DMF), and its metabolite, monomethyl fumarate (MMF), for the treatment of multiple sclerosis are not completely elucidated. To discuss the role of DMF/MMF-induced hydroxycarboxylic acid receptor 2 (HCA2/GPR109A) pathway activation in the immune response and treatment of MS. A narrative (traditional) review of the current literature. 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. 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.