琥珀酸可抗神经炎症

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

DOI：
10.1016/j.stem.2018.01.020

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.

All Authors：
Luca Peruzzotti-Jametti, Joshua D Bernstock, Nunzio Vicario, Ana SH Costa, Chee Keong Kwok, Tommaso Leonardi, Lee M Booty, Iacopo Bicci, Beatrice Balzarotti, Giulio Volpe, Giulia Mallucci, Giulia Manferrari, Matteo Donega` , Nunzio Iraci, Alice Braga, John M Hallenbeck, Michael P Murphy, Frank Edenhofer, Christian Frezza,Stefano Pluchino

First Authors：
Luca Peruzzotti-Jametti, Joshua D Bernstock, Nunzio Vicario

Correspondence：
Luca Peruzzotti-Jametti,Frank Edenhofer, Christian Frezza,Stefano Pluchino

摘要:

     在多发性硬化小鼠模型中，通过脑脊液注射移植体细胞诱导的神经干细胞（iNSC）可降低脑脊液中的琥珀酸水平、减少单核吞噬细胞（MP）浸润和继发性神经损伤，其抑制神经炎症的效果与移植神经干细胞等同； 其机制是炎性MP释放的琥珀酸可激活NSC的琥珀酸受体（SUCNR1）/GPR91，增加NSC的琥珀酸摄入以清除胞外琥珀酸；并分泌前列腺素E2诱导1型MP向抗炎性的氧化磷酸化代谢表型转变，以抑制炎症；移植Sucnr1-/-的NSC发现可严重削弱其抗炎性作用。