Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS)1,2,3. 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.
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This work was supported by grants NS087867, ES02530, AI126880 and AI093903 from the National Institutes of Health, RSG-14-198-01-LIB from the American Cancer Society and RG4111A1 and JF2161-A-5 from the National Multiple Sclerosis Society to F.J.Q. F.J.Q. and J.A. received support from International Progressive Multiple Sclerosis Alliance grant PA-1604-08459. V.R. received support from an educational grant from Mallinkrodt Pharmaceuticals (A219074) and by a fellowship from the German Research Foundation (DFG RO4866 1/1). M.P. is supported by the BMBF-funded competence network of multiple sclerosis (KKNMS), the Sobek-Stiftung and the DFG (SFB 992, SFB1140, SFB/TRR167, Reinhart-Koselleck-Grant) and the Ministry of Science, Research and the Arts, Baden-Wuerttemberg (Sonderlinie ‘Neuroinflammation’). Human fetal tissue came from the Human Fetal Tissue Repository (Albert Einstein College of Medicine) and from the University of Washington Birth Defects Research Laboratory (BDRL, Project Number 5R24HD000836-51).
Nature thanks S. Liddelow, M. Platten, H. Wekerle and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease
Nature Reviews Immunology (2019)