The rapidly evolving field of immunometabolism has shed new light on new fundamental properties of metabolites, which can regulate inflammation via ligand-receptor signalling modalities. Among these, succinate signalling via succinate receptor 1 (SUCNR1) plays a key role in controlling myeloid cells responses in systemic inflammatory conditions. However, how the succinate-SUCNR1 axis regulates myeloid cell functions in the central nervous system (CNS) inflammatory disorders, such as multiple sclerosis (MS), is still largely unknown.

Herein, I first investigated the role of SUCNR1 signalling in mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. I found that SUCNR1 expression increases in the inflamed mouse CNS, where it is mostly expressed by myeloid cells in chronic inflammatory lesions. Post mortem single-molecule fluorescence in situ hybridization (smFISH) and histopathology analysis of people with progressive MS confirmed a predominant expression of SUCNR1 in chronic active and active white matter lesions. When EAE was induced in a constitutive Sucnr1 knockout (Sucnr1-/-) mice, I found that Sucnr1-/- led to a significantly worsened disease outcome compared to controls, which was associated with increased peripheral immune infiltration and relatively lower numbers of microglia seen via ex vivo suspension mass cytometry (CyTOF) immunophenotyping. Mechanistically, I found that SUCNR1 has opposite effects on macrophages, where it attenuates their pro-inflammatory activation, compared to microglia, where it promotes the response to both pro-inflammatory stimuli and succinate stimulation in vitro. Concordantly, I found that the in vivo genetic perturbation of Sucnr1 function in microglia only was capable of attenuating EAE disease severity, ameliorating neuropathological outcomes, and promoting the acquisition of a preferential homeostatic microglial phenotype as seen via CyTOF and single-cell RNA sequencing (scRNAseq) analyses.

In conclusion, my work clarified the role of SUCNR1 as metabolic receptor of myeloid cells that drives microglial persistent activation and identified a new pathway that could be leveraged to ameliorate persistent CNS inflammation in MS.