Grzegorz Krzak, Cory M. Willis, Liviu Pirvan, Maria Repollés-de-Dalmau, Julie A. Reisz, Rosana-Bristena Ionescu, Gregory Jordan, Monica Emili Garcia-Segura, Berfin Barlas, Arianna Ghia, Alexandra M. Nicaise, Ivan Lombardi, David Rowitch, Gabriel Balmus, Alessandro D’Angelo, Sonia Fernández-Veledo, Irina Mohorianu, Stefano Pluchino, and Luca Peruzzotti-Jametti
Myeloid cells play a pivotal role in persistent central nervous system (CNS) inflammation. Succinate, a tricarboxylic acid cycle metabolite, is a major regulator of myeloid cell functions through intracellular and extracellular signaling pathways. In this study, we aimed to unravel how extracellular succinate signaling via its succinate receptor 1 (SUCNR1) modulates myeloid cell function during CNS inflammation. We revealed that SUCNR1 exerts differential effects on myeloid cells: it blunts the pro-inflammatory polarization of CNS-infiltrating macrophages while it enhances that of CNS-resident microglia. Accordingly, using microglia-specific SUCNR1 knockout mice, we obtained a significant reduction of pro-inflammatory cytokines signaling and cerebrospinal fluid succinate in a multiple sclerosis (MS)-like disease mouse model, which was coupled with decreased immune infiltration and axonal damage. We further validated the pro-inflammatory effects of microglial SUCNR1 in post-mortem MS brains and in human microglia in vitro, thus establishing its critical role in regulating myeloid responses during CNS inflammation.
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Scripts- R scripts for generating all steps of the analysis -
CyTOF data- folder containing all CyTOF data used in this study