Microglial control of astrocytes in response to microbial metabolites
Open accessAbstract
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.
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Microglia and astrocytes coordinate their functions in many ways, both in the healthy and diseased brain.
“However, recent data indicate that microglia and astrocytes coordinate their functions in many ways, both in the healthy and diseased brain [14–21].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [18]
The paper’s Abstract reports that microglial TGF-α and VEGF-B regulate astrocyte activity in an experimental model of multiple sclerosis, supporting coordination in a diseased CNS. It does not establish the broader claim that the cells coordinate their functions in many ways in both healthy and diseased brains. (LLM, conf=0.83)
Experimental — accuracy not yet measuredNanoString data confirmed increased astrocyte expression of EGFR, which has been proposed as a potential amyloid beta receptor and a regulator of astrocytes in multiple sclerosis.
“as well as increased astrocyte expression of EGFR, which has been proposed as a potential receptor for Aβ37, and a regulator of astrocytes in multiple sclerosis38.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [38]
AHR activation suppresses NF-κB signaling and inhibits CNS inflammation in experimental autoimmune encephalomyelitis mouse models of multiple sclerosis.
“The AHR activation suppresses NF-κB signaling and inhibits CNS inflammation in experimental autoimmune encephalomyelitis (EAE) mouse models of multiple sclerosis.247,248”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [247]
In the EAE mouse model of MS, peripheral metabolism of dietary tryptophan by the gut microbiota generates metabolites that dampen the ability of microglia to induce pro-inflammatory responses in astrocytes, thereby ameliorating disease.
“In a recent study using the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, peripheral metabolism of dietary tryptophan by the gut microbiota was shown to generate metabolites that dampen the ability of microglia to induce pro-inflammatory responses in astrocytes, thereby ameliorating disease (Rothhammer et al., 2018).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Rothhammer et al., 2018
IPA may control microglia-activated inflammation through a mechanism mediated by AhR.
“Recent studies suggest that IPA may control microglia-activated inflammation through a mechanism mediated by AhR (29, 37).”
From Sepsis-Induced Gut Dysbiosis Mediates the Susceptibility to Sepsis-Associated Encephalopathy in Mice (2022) · cites this paper as [37]
AhR activation can drive macrophages to acquire an immune-suppressive phenotype.
“AhR activation can drive macrophages to acquire an immune-suppressive phenotype.”
From Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity (2022) · cites this paper as Rothhammer et al., 2018
Expression of numerous efferocytosis/clearance-associated genes in cerebellar microglia comprises a set encoding transcription factors implicated in regulation of macrophage polarization, clearance, and differentiation, including AHR, TFEC, and RARG.
“The expression of numerous efferocytosis/clearance-associated genes in cbMg comprises a set that encodes transcription factors implicated in the regulation of macrophage polarization, clearance, and differentiation, including AHR36, TFEC37, and RARG38.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [36]
Tryptophan, a serotonin precursor, influences microglia activity.
“Another microbial metabolite that influences microglia activity is tryptophan, a serotonin precursor (89).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [89]
Bacterial metabolites derived from dietary tryptophan can control CNS inflammation through an aryl hydrocarbon receptor-mediated mechanism acting on microglial activation and the transcriptional program of astrocytes.
“Bacterial metabolites derived from dietary tryptophan could control the CNS inflammation through an aryl hydrocarbon receptor (Ahr)-mediated mechanism acting on microglial activation and the transcriptional program of astrocytes (89).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [89]
Tryptophan or indoxyl-3-sulfate treatment ameliorated experimental autoimmune encephalomyelitis scores in control mice but not in mice lacking AhR expression on microglia fed a tryptophan-deficient diet.
“Briefly, Trp or I3S treatment ameliorated EAE scores in control mice but not in mice lacking AhR expression on the microglia fed with Trp-deficient diet (89).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [89]
Microglia have a crucial role in the mechanism of protection from experimental autoimmune encephalomyelitis via the tryptophan-AhR pathway.
“A couple of years later, the same group discovered that the microglia has a crucial role in this mechanism of protection from EAE via the Trp-AhR pathway (89).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [89]
AhR, TGF-α, and VEGF-β expression were detected on myeloid CD14+ cells in demyelinated active and chronic multiple sclerosis lesions of patients.
“Finally, they detected AhR, TGF-α, and VEGF-β expression on myeloid CD14+ cells in the demyelinated active and chronic MS lesions of patients (89).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [89]
In vitro stimulation with indoxyl-3-sulfate activated the AhR signaling pathway in primary human microglia, leading to suppression of pro-inflammatory pathways via TNF-α, IL-6, IL-12A, NOS2, and VEGF-β expression and promotion of anti-inflammatory responses such as IL-10 and TGF-α expression.
“Moreover, using primary human microglia, they showed that the in vitro stimulation with I3S activated the AhR signaling pathway leading to the suppression of pro-inflammatory pathways (via TNF-α, IL-6, IL-12A, NOS2, VEGF-β expression), and the promotion of anti-inflammatory responses (such as IL-10 and TGF-α expression) (89).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [89]
Treatment initiated 14 days after experimental autoimmune encephalomyelitis induction ameliorated the disease via AhR engagement on astrocytes and microglia.
“This treatment was initiated 14 days after EAE induction and ameliorated the disease via AhR engagement on astrocytes and microglia (89).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [89]
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“In a recent study using the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, peripheral metabolism of dietary tryptophan by the gut microbiota was shown to generate metabolites that dampen the ability of microglia to induce pro-inflammatory responses in astrocytes, thereby ameliorating disease (Rothh…”
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- Authors
- Rothhammer, V., Borucki, D. M., Tjon, E. C., Takenaka, M. C., Chao, C.-C., Ardura-Fabregat, A., de Lima, K. A., Gutiérrez-Vázquez, C., Hewson, P., Staszewski, O., Blain, M., Healy, L., Neziraj, T., Borio, M., Wheeler, M., Dragin, L. L., Laplaud, D. A., Antel, J., Alvarez, J. I., Prinz, M., & Quintana, F. J.
- Affiliations
- Brigham and Women's Hospital (US)
- University of Freiburg (DE)
- Montreal Neurological Institute and Hospital (CA)
- Inserm (FR)
- University of Pennsylvania (US)
- Broad Institute (US)
- Corresponding author
- Quintana, Francisco J.
- ORCID
- Venue
- Nature
- Published
- 2018-05
- Volume
- 557
- Issue
- 7707
- Pages
- 724-728
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6422159
- OpenAlex
- W2803938554
- Cited by
- 1,051
- References
- 35
- Citations by year
- 2026: 82 · 2025: 132 · 2024: 131 · 2023: 154 · 2022: 155 · 2021: 138 · 2020: 124 · 2019: 97 · 2018: 37
- FWCI
- 44.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- National Institutes of Health (ES02530, AI093903)
- National Cancer Institute (T32CA207021)
- National Institute of Allergy and Infectious Diseases (R01AI093903, R56AI093903, R01AI126880)
- National Institute of Neurological Disorders and Stroke (R01NS102807, R21NS087867)
- National Institute of Environmental Health Sciences (R01ES025530)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R24HD000836)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- microglia, astrocytes, transforming growth factor-alpha, VEGF-B, experimental autoimmune encephalomyelitis, multiple sclerosis, tryptophan metabolites, commensal gut microbiota, aryl hydrocarbon receptor, neuroinflammation, microglial activation
- MeSH terms
- Animals, Astrocytes, Cells, Cultured, Central Nervous System, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Female, Humans, Inflammation, Mice, Inbred C57BL, Multiple Sclerosis, Symbiosis, Tryptophan, Transforming Growth Factor alpha, Microglia, Receptors, Aryl Hydrocarbon, Lipopolysaccharide Receptors, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factor B, Mice, ErbB Receptors
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