Microglial control of astrocytes in response to microbial metabolites
- PMID: 29769726
- PMCID: PMC6422159
- DOI: 10.1038/s41586-018-0119-x
Microglial control of astrocytes in response to microbial metabolites
Abstract
Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS)1-3. Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood4,5. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14+ cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.
Conflict of interest statement
Competing financial interests
The authors declare no competing financial interests.
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Comment in
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Brain inflammatory cascade controlled by gut-derived molecules.Nature. 2018 May;557(7707):642-643. doi: 10.1038/d41586-018-05113-0. Nature. 2018. PMID: 29805157 No abstract available.
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Modulating microglia.Nat Rev Neurosci. 2018 Jul;19(7):387. doi: 10.1038/s41583-018-0027-y. Nat Rev Neurosci. 2018. PMID: 29880846 No abstract available.
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