Microglial control of astrocytes in response to microbial metabolites.
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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|PubMed Central ID||
R01 NS102807 / NS / NINDS NIH HHS / United States
R01 ES025530 / ES / NIEHS NIH HHS / United States
R01 AI126880 / AI / NIAID NIH HHS / United States
AI093903 / NH / NIH HHS / United States
R56 AI093903 / AI / NIAID NIH HHS / United States
R21 NS087867 / NS / NINDS NIH HHS / United States
R01 AI093903 / AI / NIAID NIH HHS / United States
AI126880 / NH / NIH HHS / United States
ES02530 / NH / NIH HHS / United States
T32 CA207021 / CA / NCI NIH HHS / United States
NS087867 / NH / NIH HHS / United States
R24 HD000836 / HD / NICHD NIH HHS / United States