Macrophage-derived extracellular succinate licenses neural stem cells to suppress chronic neuroinflammation
Open accessAbstract
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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NSCs with myeloid cells or astrocytes co-cultures examine how immune and glial cells influence NSC and NPC proliferation, differentiation and reparative capacity, informing strategies to modulate endogenous repair and glial scar formation.
“Such systems examine how immune and glial cells influence NSC and neural progenitor cell (NPC) proliferation, differentiation and reparative capacity75,76, informing strategies to modulate endogenous repair and glial scar formation77.”
From From insights to innovations: evaluating preclinical paradigms in demyelinating disease therapeutics (2026) · cites this paper as [75]
The STAR Methods (page unavailable) describe NSC–macrophage co-cultures, and the Results report NSC responses to macrophage-derived succinate and reduced inflammation after NSC transplantation. The paper does not show these co-cultures examining how myeloid cells affect NSC or NPC proliferation and differentiation, nor does it describe astrocyte co-cultures. Glial scar formation is attached to citation 77, not this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredsEVs can have intrinsic metabolic activity.
“It has previously been reported that sEVs can have intrinsic metabolic activity (Iraci et al., 2017, Peruzzotti-Jametti et al., 2018, Yoshida et al., 2019).”
From Small Extracellular Vesicles Have GST Activity and Ameliorate Senescence-Related Tissue Damage (2020) · cites this paper as Peruzzotti-Jametti et al., 2018
EVs have asparaginase and succinase activity to suppress neuroinflammation.
“EVs have been shown to have asparaginase and succinase activity to suppress neuroinflammation (Iraci et al., 2017, Peruzzotti-Jametti et al., 2018)”
From Small Extracellular Vesicles Have GST Activity and Ameliorate Senescence-Related Tissue Damage (2020) · cites this paper as Peruzzotti-Jametti et al., 2018
In the presence of oxygen, conserved proline residues in HIF-1α are hydroxylated by PHD 1, 2 and 3, providing a recognition site for VHL E3 ubiquitin ligase, which ubiquitinates HIF-1α and targets it for proteasomal degradation.
“In the presence of oxygen, conserved proline residues in the HIF-1α subunit are hydroxylated by PHD 1, 2 and 3 16. Hydroxylation provides a recognition site for the binding of Von Hippel-Lindau (VHL) E3 ubiquitin ligase, which ubiquitinates HIF-1α and subsequently targets it for proteasomal degradation17.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [16]
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References 67 · Cited by 285
- Authors
- Peruzzotti-Jametti, L., Bernstock, J. D., Vicario, N., Costa, A. S. H., Kwok, C. K., Leonardi, T., Booty, L. M., Bicci, I., Balzarotti, B., Volpe, G., Mallucci, G., Manferrari, G., Donegà, M., Iraci, N., Braga, A., Hallenbeck, J. M., Murphy, M. P., Edenhofer, F., Frezza, C., & Pluchino, S.
- Affiliations
- National Institutes of Health (US)
- University of Cambridge (GB)
- University of Würzburg (DE)
- Universität Innsbruck (AT)
- Corresponding author
- Edenhofer, Frank
- Frezza, Christian
- Pluchino, Stefano
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 22
- Issue
- 3
- Pages
- 355-368.e13
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC5842147
- OpenAlex
- W2788731808
- Cited by
- 285
- References
- 67
- Citations by year
- 2026: 30 · 2025: 22 · 2024: 28 · 2023: 27 · 2022: 34 · 2021: 55 · 2020: 42 · 2019: 31 · 2018: 15 · 2017: 1
- FWCI
- 16.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- The Novartis Repository (Novartis) (submittedVersion)
- Apollo (cc-by)
- Funders
- Congressionally Directed Medical Research Programs (MS140019)
- U.S. Department of Defense
- Wellcome Trust (RRZA/057 RG79423)
- Austrian Science Fund
- Evelyn Trust (RG 69865)
- Biotechnology and Biological Sciences Research Council (MR/K026682/1)
- European Research Council
- Medical Research Council
- Engineering and Physical Sciences Research Council
- Associazione Italiana Sclerosi Multipla (2010/R/31, 2014/PMS/4)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- neural stem cells, immunometabolism, chronic neuroinflammation, mononuclear phagocytes, prostaglandin E2, stem cell transplantation, cerebrospinal fluid metabolites, anti-inflammatory activity, neuroprotection
- MeSH terms
- Animals, Cell Line, Central Nervous System, Chronic Disease, Female, Humans, Inflammation, Macrophages, Mice, Inbred C57BL, Oxidative Phosphorylation, Dinoprostone, Succinic Acid, Receptors, G-Protein-Coupled, Neural Stem Cells
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