Microglial control of astrocytes in response to microbial metabolites

Veit Rothhammer, Davis M. Borucki, Emily C. Tjon, Maisa C. Takenaka, Chun-Cheih Chao, Alberto Ardura-Fabregat, Kalil Alves de Lima, Cristina Gutiérrez-Vázquez, 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 and Francisco J. Quintana ()
Additional contact information
Veit Rothhammer: Harvard Medical School
Davis M. Borucki: Harvard Medical School
Emily C. Tjon: Harvard Medical School
Maisa C. Takenaka: Harvard Medical School
Chun-Cheih Chao: Harvard Medical School
Alberto Ardura-Fabregat: University of Freiburg
Kalil Alves de Lima: Harvard Medical School
Cristina Gutiérrez-Vázquez: Harvard Medical School
Patrick Hewson: Harvard Medical School
Ori Staszewski: University of Freiburg
Manon Blain: McGill University
Luke Healy: McGill University
Tradite Neziraj: Harvard Medical School
Matilde Borio: Harvard Medical School
Michael Wheeler: Harvard Medical School
Loic Lionel Dragin: University of Pennsylvania
David A. Laplaud: INSERM
Jack Antel: McGill University
Jorge Ivan Alvarez: University of Pennsylvania
Marco Prinz: University of Freiburg
Francisco J. Quintana: Harvard Medical School

Nature, 2018, vol. 557, issue 7707, 724-728

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41586-018-0119-x

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