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

Cell Stem Cell
Luca Peruzzotti-JamettiStefano Pluchino

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.

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Datasets Mentioned

BETA
E-MTAB-5579
E-MTAB-5586

Methods Mentioned

BETA
Confocal microscopy
flow cytometry
FACS
Assay
ELISA
Protein assay
electrophoresis
chips
Chip
PCR

Software Mentioned

ArrayExpress
GraphPad Prism
GraphPad
Treestar
Affymetrix
XCalibur Quan Browser
Affymetrix AGCC
SPSS
XCalibur Qual Browser
R

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