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. Mice on normal chow (NC) diet, in contrast, and even more so mice on high-fiber (HFb) diet showed the expected protective DMF effect. 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 (HCAR2) which is highly expressed in neutrophil granulocytes. Indeed, deletion of Hcar2 in neutrophils abrogated DMF protective effects in EAE. Diet had a profound effect on the transcriptional profile of neutrophils and modulated their response to MMF. In summary, DMF required HCAR2 on neutrophils as well as permissive dietary effects for its therapeutic action. Translating the dietary intervention into the clinic may improve MS therapy.

Neurovascular coupling, linking neuronal activity to cerebral blood flow, is essential for brain function and underpins functional brain imaging. Whereas mechanisms involved in vasodilation are well-documented, those controlling vasoconstriction remain overlooked. This study unravels the mechanisms by which pyramidal cells elicit arteriole vasoconstriction. Using patch-clamp recording, vascular and Ca²⁺ imaging in mouse cortical slices, we show that strong optogenetic activation of layer II/III pyramidal cells induces vasoconstriction, correlating with firing frequency and somatic Ca²⁺ increase. Ex vivo and in vivo pharmacological investigations indicate that this vasoconstriction predominantly recruits prostaglandin E2 through the cyclooxygenase-2 pathway, and activation of EP1 and EP3 receptors. We also present evidence that specific interneurons releasing neuropeptide Y, and astrocytes, through 20-hydroxyeicosatetraenoic acid, contribute to this process. By revealing the mechanisms by which pyramidal cells lead to vasoconstriction, our findings shed light on the complex regulation of neurovascular coupling.