Cited by 331Neuroinflammation and Neurodegeneration Mechanismsinterferon and immune responsesImmune Cell Function and Interaction

Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes

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Sanmarco, Liliana M., Wheeler, Michael A., Gutiérrez-Vázquez, Cristina, Polonio, Carolina Manganeli, Linnerbauer, Mathias, Pinho-Ribeiro, Felipe A., Li, Zhaorong, Giovannoni, Federico +10 more·2021·Nature

Abstract

Astrocytes are glial cells that are abundant in the central nervous system (CNS) and that have important homeostatic and disease-promoting functions 1. However, little is known about the homeostatic anti-inflammatory activities of astrocytes and their regulation. Here, using high-throughput flow cytometry screening, single-cell RNA sequencing and CRISPR-Cas9-based cell-specific in vivo genetic perturbations in mice, we identify a subset of astrocytes that expresses the lysosomal protein LAMP1 2 and the death receptor ligand TRAIL 3. LAMP1+TRAIL+ astrocytes limit inflammation in the CNS by inducing T cell apoptosis through TRAIL-DR5 signalling. In homeostatic conditions, the expression of TRAIL in astrocytes is driven by interferon-γ (IFNγ) produced by meningeal natural killer (NK) cells, in which IFNγ expression is modulated by the gut microbiome. TRAIL expression in astrocytes is repressed by molecules produced by T cells and microglia in the context of inflammation. Altogether, we show that LAMP1+TRAIL+ astrocytes limit CNS inflammation by inducing T cell apoptosis, and that this astrocyte subset is maintained by meningeal IFNγ+ NK cells that are licensed by the microbiome.

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Crossref · 10.1038/s41586-020-03116-4

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  • The gut microbiota restricts neuroinflammation by promoting anti-inflammatory TRAIL+ astrocytes and inducing T-cell apoptosis via TRAIL-DR5 signaling.

    “Furthermore, the gut microbiota is involved in restricting neuroinflammation by promoting anti-inflammatory tumor necrosis factor-related apoptosis-inducing ligand-positive (TRAIL+) astrocytes and inducing T-cell apoptosis via TRAIL-death receptor 5 (DR5) signaling.250”

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Authors
Sanmarco, L. M., Wheeler, M. A., Gutiérrez-Vázquez, C., Polonio, C. M., Linnerbauer, M., Pinho-Ribeiro, F. A., Li, Z., Giovannoni, F., Batterman, K. V., Scalisi, G., Zandee, S. E. J., Heck, E. S., Alsuwailm, M., Rosene, D. L., Becher, B., Chiu, I. M., Prat, A., & Quintana, F. J.
Affiliations
  • Brigham and Women's Hospital (US)
  • Broad Institute (US)
  • Harvard University (US)
  • Boston University (US)
  • University of Zurich (CH)
  • Centre Hospitalier de l’Université de Montréal (CA)
Corresponding author
Quintana, Francisco J.
Venue
Nature
Published
2021-01-06
Volume
590
Issue
7846
Pages
473-479
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W3118771939
Cited by
331
References
91
Citations by year
2026: 42 · 2025: 66 · 2024: 56 · 2023: 64 · 2022: 59 · 2021: 44
FWCI
23.43
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Conicet (submittedVersion, cc-by-nc-sa)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • National Cancer Institute (P30CA006516)
  • National Institute of Allergy and Infectious Diseases (R01AI149699, R01AI130019, R01AI126880)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK127257)
  • National Institute of Neurological Disorders and Stroke (F32NS101790, R01NS102807, K99NS114111)
  • National Institute of Environmental Health Sciences (R01ES029136)
  • National Center for Complementary and Integrative Health (DP2AT009499)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
Keywords
astrocytes, LAMP1, TRAIL, interferon-gamma, gut microbiota, neuroinflammation, T cell apoptosis, meningeal immunity, microglia, T cell homeostasis
MeSH terms
Gastrointestinal Microbiome, Animals, Astrocytes, Central Nervous System, Encephalomyelitis, Autoimmune, Experimental, Female, Homeostasis, Humans, Inflammation, Interferon-gamma, Killer Cells, Natural, Meninges, Mice, Inbred C57BL, T-Lymphocytes, Biomarkers, Apoptosis, Mice, Lysosomal Membrane Proteins, Lysosomal-Associated Membrane Protein 1, TNF-Related Apoptosis-Inducing Ligand

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