Diet modulates the protective effects of dimethyl fumarate mediated by the immunometabolic neutrophil receptor HCA2

Monomethyl fumarate (MMF) and its prodrug dimethyl fumarate (DMF) are currently the most widely used agents for the treatment of multiple sclerosis (MS). However, not all patients benefit from DMF. We hypothesized that the variable response of patients may be due to their diet. In support of this hypothesis, mice subjected to experimental autoimmune encephalomyelitis (EAE), a model of MS, did not benefit from DMF treatment when fed a lauric acid-rich (LA) diet, in contrast to normal chow (NC) or, more so, a high-fiber (HFb) diet. DMF lacked efficacy in the LA diet fed group despite similar resorption and preserved effects on plasma lipids. When mice were fed the permissive HFb diet, the protective effect of DMF treatment depended on hydroxycarboxylic receptor 2 (HCA2) which is highly expressed in neutrophil granulocytes. Indeed, deletion of Hca2 in neutrophils abrogated DMF protective effects. Diet had a profound effect on the transcriptional profile of neutrophils and modulated their response to MMF. In summary, DMF required HCA2 on neutrophils as well as permissive dietary effects for its therapeutic action. Translating the dietary intervention into the clinic may improve MS therapy.