Microglial control of astrocytes in response to microbial metabolites

• Published in: Nature (London) 2018-05, Vol.557 (7707), p.724-728
• Main Authors: Rothhammer, Veit, Borucki, Davis M., Tjon, Emily C., Takenaka, Maisa C., Chao, Chun-Cheih, Ardura-Fabregat, Alberto, de Lima, Kalil Alves, Gutiérrez-Vázquez, Cristina, Hewson, Patrick, Staszewski, Ori, Blain, Manon, Healy, Luke, Neziraj, Tradite, Borio, Matilde, Wheeler, Michael, Dragin, Loic Lionel, Laplaud, David A., Antel, Jack, Alvarez, Jorge Ivan, Prinz, Marco, Quintana, Francisco J.
• Format: Article
• Language: English
• Subjects: 38/91; 631/250/262; 631/250/371; Alzheimer's disease; Analysis; Angiogenesis; Animals; Aromatic compounds; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Bone marrow; CD14 antigen; Cells, Cultured; Central nervous system; Central Nervous System - metabolism; Central Nervous System - microbiology; Central Nervous System - pathology; Disease Models, Animal; Encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - microbiology; Encephalomyelitis, Autoimmune, Experimental - pathology; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Endothelial growth factors; ErbB Receptors - metabolism; ErbB-1 protein; Experimental allergic encephalomyelitis; Female; Flora; Gene expression; Humanities and Social Sciences; Humans; Hydrocarbons; Immunology; Inflammation; Inflammation - metabolism; Inflammation - microbiology; Inflammation - pathology; Inflammation - prevention & control; Letter; Life Sciences; Lipopolysaccharide Receptors - metabolism; Lymphocytes B; Metabolites; Mice; Mice, Inbred C57BL; Microbiological research; Microglia; Microglia - metabolism; Microglia - pathology; Microorganisms; multidisciplinary; Multiple sclerosis; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Nervous system; Nervous system diseases; Neurodegeneration; Neurological diseases; Neurotoxicity; Physiological aspects; Receptors, Aryl Hydrocarbon - metabolism; Recruitment; Regulators; Science; Science (multidisciplinary); Signal transduction; Spinal cord injuries; Symbiosis; Transcription; Transforming Growth Factor alpha - biosynthesis; Transforming Growth Factor alpha - metabolism; Transforming growth factors; Tryptophan; Tryptophan - deficiency; Tryptophan - metabolism; Vascular endothelial growth factor; Vascular Endothelial Growth Factor B - biosynthesis; Vascular Endothelial Growth Factor B - metabolism; Vascular Endothelial Growth Factor Receptor-1 - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0119-x

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 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. TGFα and VEGF-B produced by microglia regulate astrocyte function in the experimental autoimmune encephalomyelitis model of multiple sclerosis.