Journal
NATURE
Volume 557, Issue 7707, Pages 724-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-018-0119-x
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Funding
- National Institutes of Health [NS087867, ES02530, AI126880, AI093903]
- American Cancer Society [RSG-14-198-01-LIB]
- National Multiple Sclerosis Society [RG4111A1, JF2161-A-5]
- International Progressive Multiple Sclerosis Alliance grant [PA-1604-08459]
- Mallinkrodt Pharmaceuticals [A219074]
- German Research Foundation (DFG) [RO4866 1/1]
- BMBF
- Sobek-Stiftung
- DFG [SFB 992, SFB1140, SFB/TRR167]
- Ministry of Science, Research and Arts, Baden-Wuerttemberg
- University of Washington Birth Defects Research Laboratory (BDRL) [5R24HD000836-51]
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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 understood(4,5). Here we report that TGF alpha 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 TGFa 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 alpha also participate in the microglial control of human astrocytes. Furthermore, expression of TGF alpha 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 alpha 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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