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

Peruzzotti-Jametti, Luca and Bernstock, Joshua D and Vicario, Nunzio and Costa, Ana SH and Kwok, Chee-Keong and Leonardi, Tommaso and Booty, Lee and Bicci, Iacopo and Balzarotti, Beatrice and Volpe, Giulio and Mallucci, Giulia and Manferrari, Giulia and Donega, Matteo and Iraci, Nunzio and Braga, Alice and Hallenbeck, John M and Murphy, Michael P and Edenhofer, Frank and Freeza, Christian and Pluchino, Stefano (2018) Macrophage-Derived Extracellular Succinate Licenses Neural Stem Cells to Suppress Chronic Neuroinflammation. Cell Stem Cell, 22 (3). 355-368.e13. ISSN 18759777

Abstract

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. 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.

Item Type: Article
Keywords: cell metabolism experimental autoimmune encephalomyelitis inflammation macrophages microglia multiple sclerosis neural stem cells regenerative medicine stem cells succinate
Date Deposited: 20 Apr 2018 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/32451

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