Microglial control of astrocytes in response to microbial metabolites

• DOI: 10.1038/s41586-018-0119-x
• Publication Date: 2018-05-14T11:24:29Z
• Authors: Veit Rothhammer; Davis M. Borucki; Emily C. Tjon; Maisa C. Takenaka; Chun-Cheih Chao; Alberto Ardura-Fa...; Kalil Alves de Lima; Cristina Gutiérre...; Patrick Hewson; Ori Staszewski; Manon Blain; Luke Healy; Tradite Neziraj; Matilde Borio; Michael Wheeler; Loic Lionel Dragin; David A. Laplaud; Jack Antel; Jorge Ivan Alvarez; Marco Prinz; Francisco J. Quin...
• Keywords: Central Nervous System; Vascular Endothelial Growth Factor B; Encephalomyelitis, Autoimmune, Experimental; Multiple Sclerosis; [SDV.IMM] Life Sciences [q-bio]/Immunology; Lipopolysaccharide Receptors; 610; Mice; 03 medical and health sciences; Team4; Animals; Humans; CRTI; Symbiosis; Cells, Cultured; Inflammation; 0303 health sciences; Tryptophan; Transforming Growth Factor alpha; 3. Good health; ErbB Receptors; Mice, Inbred C57BL; Disease Models, Animal; Receptors, Aryl Hydrocarbon; Astrocytes; [SDV.IMM]Life Sciences [q-bio]/Immunology; Female; Microglia

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 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.