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

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

doi:10.1016/j.stem.2018.01.020

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

Cell Stem Cell. 2018 Mar 1;22(3):355-368.e13. doi: 10.1016/j.stem.2018.01.020. Epub 2018 Feb 22.

Authors

Luca Peruzzotti-Jametti¹, Joshua D Bernstock², Nunzio Vicario³, Ana S H Costa⁴, Chee Keong Kwok⁵, Tommaso Leonardi³, Lee M Booty⁶, Iacopo Bicci³, Beatrice Balzarotti³, Giulio Volpe³, Giulia Mallucci³, Giulia Manferrari³, Matteo Donegà³, Nunzio Iraci⁷, Alice Braga³, John M Hallenbeck⁸, Michael P Murphy⁶, Frank Edenhofer⁹, Christian Frezza¹⁰, Stefano Pluchino¹¹

Affiliations

¹ Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK. Electronic address: lp429@cam.ac.uk.
² Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK; Stroke Branch, National Institute of Neurological Disorders and Stroke, NIH (NINDS/NIH), Bethesda, MD, USA.
³ Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK.
⁴ MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
⁵ Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany.
⁶ MRC Mitochondrial Biology Unit, Hills Road, University of Cambridge, Cambridge, UK.
⁷ Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK; Department of Biomedical and Biotechnological Sciences (BIOMETEC), University of Catania, Via S. Sofia 97, Catania 95125, Italy.
⁸ Stroke Branch, National Institute of Neurological Disorders and Stroke, NIH (NINDS/NIH), Bethesda, MD, USA.
⁹ Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany; Institute of Molecular Biology and CMBI, Genomics, Stem Cell Biology and Regenerative Medicine, Leopold-Franzens-University Innsbruck, Innsbruck, Austria. Electronic address: frank.edenhofer@uibk.ac.at.
¹⁰ MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK. Electronic address: cf366@mrc-cu.cam.ac.uk.
¹¹ Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK. Electronic address: spp24@cam.ac.uk.

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.

Keywords: cell metabolism; experimental autoimmune encephalomyelitis; inflammation; macrophages; microglia; multiple sclerosis; neural stem cells; regenerative medicine; stem cells; succinate.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Line
Central Nervous System / pathology*
Chronic Disease
Dinoprostone / metabolism
Female
Humans
Inflammation / pathology*
Macrophages / metabolism*
Mice, Inbred C57BL
Neural Stem Cells / cytology*
Neural Stem Cells / transplantation
Oxidative Phosphorylation
Receptors, G-Protein-Coupled / metabolism
Succinic Acid / cerebrospinal fluid
Succinic Acid / metabolism*

Substances

GPR91 protein, mouse
Receptors, G-Protein-Coupled
SUCNR1 protein, human
Succinic Acid
Dinoprostone

Abstract

Publication types

MeSH terms

Substances

Grants and funding