Microglial control of astrocytes in response to microbial metabolites

V Rothhammer, DM Borucki, EC Tjon, MC Takenaka… - Nature, 2018 - nature.com
V Rothhammer, DM Borucki, EC Tjon, MC Takenaka, CC Chao, A Ardura-Fabregat…
Nature, 2018nature.com
Microglia and astrocytes modulate inflammation and neurodegeneration in the central
nervous system (CNS),–. Microglia modulate pro-inflammatory and neurotoxic activities in
astrocytes, but the mechanisms involved are not completely understood,. 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 …
Abstract
Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS), –. Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood,. 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.
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