Microglial control of astrocytes in response to microbial metabolites

By Veit Rothhammer, Davis M. Borucki, Emily C. Tjon, M. Takenaka, C. Chao, Alberto Ardura Fabregat, Kalil Alves de Lima, Cristina Gutierrez Vazquez, Patrick Hewson, O. Staszewski and 11 more. Nature, 2018

899 citations recorded by the source corpus.

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

Subfields: Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/f76005f21990a17c5f499a8cc294de3f7ba0f39a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Michael A. Wheeler
2. M. Linnerbauer
3. F. Quintana
4. M. Sofroniew

In Neurology

1. F. Quintana
2. Michael A. Wheeler
3. M. Linnerbauer
4. M. Sofroniew
5. J. Burda
6. M. Pekny
7. M. Pekna

Citations in the corpus

• Astrocyte crosstalk in CNS inflammation (2020, background): “Astrocytes, microglia, and their interactions control CNS physiology in health and disease (Colombo and Farina, 2016; Glass and Saijo, 2010; Goldmann and Prinz, 2013; Keren-Shaul et al., 2017; Liddelow and Barres, 2017; Prinz et al., 2019; Rothhammer et al., 2018; Rothhammer and Quintana, 2019; Sofr”
• Astrocyte reactivity: Subtypes, states and functions in CNS innate immunity (2020, background): “Astrocytes exchange molecular signals and interact directly with other innate immune cells such as microglia [91], various perivascular cells and blood borne leukocytes [8, 32].”
• The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology (2020, methodology): “Finally, they detected AhR, TGF-a, and VEGF-b expression onmyeloid CD14 cells in the demyelinated active and chronicMS lesions of patients (89).”