Macrophage-Derived Extracellular Succinate Licenses Neural Stem Cells to Suppress Chronic Neuroinflammation

Publication date: Available online 22 February 2018
Source:Cell Stem Cell
Author(s): Luca Peruzzotti-Jametti, Joshua D. Bernstock, Nunzio Vicario, Ana S.H. Costa, Chee Keong Kwok, Tommaso Leonardi, Lee M. Booty, Iacopo Bicci, Beatrice Balzarotti, Giulio Volpe, Giulia Mallucci, Giulia Manferrari, Matteo Donegà, Nunzio Iraci, Alice Braga, John M. Hallenbeck, Michael P. Murphy, Frank Edenhofer, Christian Frezza, Stefano Pluchino
Neural stem cell (NSC) transplantation can influence immune responses and suppress inflammation in the CNS. Metabolites, such as succinate, modulate the phenotype and function of immune cells, but whether and how NSCs are also activated by such immunometabolites to control immunoreactivity and inflammatory responses is unclear. Here, we show that transplanted somatic and directly induced NSCs ameliorate chronic CNS inflammation by reducing succinate levels in the cerebrospinal fluid, thereby decreasing mononuclear phagocyte (MP) infiltration and secondary CNS damage. Inflammatory MPs release succinate, which activates succinate receptor 1 (SUCNR1)/GPR91 on NSCs, leading them to secrete prostaglandin E2 and scavenge extracellular succinate with consequential anti-inflammatory effects. Thus, our work reveals an unexpected role for the succinate-SUCNR1 axis in somatic and directly induced NSCs, which controls the response of stem cells to inflammatory metabolic signals released by type 1 MPs in the chronically inflamed brain.

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Teaser

Peruzzotti-Jametti et al. demonstrate that somatic and directly induced brain stem cells injected into the cerebrospinal fluid of mice with experimental multiple sclerosis ameliorate chronic neuroinflammation. Grafted stem cells use SUCNR1 to decrease the inflammatory metabolite succinate, thus inducing a metabolic switch in endogenous macrophages and microglia toward an anti-inflammatory phenotype.


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