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Microglial control of astrocytes in response to microbial metabolites

Rothhammer, V;Borucki, DM;Tjon, EC;Takenaka, MC;Chao, CC;Ardura-Fabregat, A;de Lima, KA;Gutirrez-Vzquez, C;Hewson, P;Staszewski, O;Blain, M;Healy, L;Neziraj, T;Borio, M;Wheeler, M;Dragin, LL;Laplaud, DA;Antel, J;Alvarez, JI;Prinz, M;Quintana, FJ;

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 TGF 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 TGF 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 TGF also participate in the microglial control of human astrocytes. Furthermore, expression of TGF 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 TGF 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.