Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes
Open accessAbstract
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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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”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [250]
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Groß, C. C., Schulte‐Mecklenbeck, A., Wiendl, H., Marcenaro, E., de Rosbo, N. K., Uccelli, A., & Laroni, A. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00606 · Cited by 96 · see citing works
Enhancement of IFNγ Production by Distinct Commensals Ameliorates Salmonella-Induced Disease
Thiemann, S., Smit, N., Roy, U., Lesker, T. R., Gálvez, E. J. C., Koblitz, J., Basic, M., Bleich, A., Goodman, A. L., Kalinke, U., et al. (2017) · Cell Host & Microbe · doi:10.1016/j.chom.2017.05.005 · Cited by 93 · see citing works
Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10
Rojas, O. L., Pröbstel, A., Porfilio, E. A., et al. (2019) · Cell · doi:10.1016/j.cell.2019.03.037 · Cited by 93 · see citing works
The Gut–CNS Axis in Multiple Sclerosis
Kadowaki, A., & Quintana, F. J. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.06.002 · Cited by 92 · see citing works
Self-citationPurification of Rat and Mouse Astrocytes by ImmunopanningPreprint
Foo, L. C. (2013) · Cold Spring Harbor Protocols · doi:10.1101/pdb.prot074211 · Cited by 62 · see citing works
Zeine, R. R., & Owens, T. (1993) · Journal of Neuroimmunology · doi:10.1016/0165-5728(93)90042-w · Cited by 36 · see citing works
Comparative analysis of droplet-based ultra-high-throughput single-cell RNA-seq systemsPreprint
Zhang, X., Li, T., Liu, F., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/313130 · Cited by 30 · see citing works
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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193 · see citing works
Function and therapeutic value of astrocytes in neurological diseases
Lee, H.-G., Wheeler, M. A., & Quintana, F. J. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00390-x · Cited by 662 · see citing works
Self-citationThe gut microbiome in Alzheimer’s disease: what we know and what remains to be explored
Chandra, S., Sisodia, S. S., & Vassar, R. J. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00595-7 · Cited by 278 · see citing works
Lipid-accumulated reactive astrocytes promote disease progression in epilepsy
Chen, Z.-P., Wang, S., Zhao, X., Fang, W., Wang, Z., Ye, H., Wang, M.-J., Ke, L., Huang, T., Lv, P., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01288-6 · Cited by 214 · see citing works
APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints
Yin, Z., Rosenzweig, N., Kleemann, K. L., Zhang, X., Brandão, W., Margeta, M. A., Schroeder, C., Sivanathan, K. N., Silveira, S., Gauthier, C., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01627-6 · Cited by 202 · see citing works
Repositioning TH cell polarization from single cytokines to complex help
Tuzlak, S., Dejean, A. S., Iannacone, M., Quintana, F. J., Waisman, A., Ginhoux, F., Korn, T., & Becher, B. (2021) · Nature Immunology · doi:10.1038/s41590-021-01009-w · Cited by 171 · see citing works
Self-citationMicrobiota–neuroepithelial signalling across the gut–brain axis
Ohara, T. E., & Hsiao, E. Y. (2025) · Nature Reviews Microbiology · doi:10.1038/s41579-024-01136-9 · Cited by 147 · see citing works
The Gut Microbiome as a Regulator of the Neuroimmune Landscape
Yu, L. W., Agirman, G., & Hsiao, E. Y. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101320-014237 · Cited by 75 · see citing works
Calì, C., Cantando, I., Veloz Castillo, M. F., Gonzalez, L., & Bezzi, P. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25168922 · Cited by 66 · see citing works
Chandra, S., Di Meco, A., Dodiya, H. B., Popovic, J., Cuddy, L. K., Weigle, I. Q., Zhang, X., Sadleir, K., Sisodia, S. S., & Vassar, R. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00635-2 · Cited by 58 · see citing works
Glucocorticoids and natural killer cells: A suppressive relationship
Muscari, I., Fierabracci, A., Adorisio, S., Moretti, M., Cannarile, L., Thi Minh Hong, V., Ayroldi, E., & Delfino, D. V. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.114930 · Cited by 32 · see citing works
Jia, X., Chen, Q., Zhang, Y., & Asakawa, T. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1296713 · Cited by 22 · see citing works
Aldh1l1-Cre/ERT2 is expressed in unintended cell types of the salivary gland, pancreas, and spleen.
Nemeth, D., Luqman, N., Chen, L., & Quan, N. (2023) · microPublication Biology · doi:10.17912/micropub.biology.000832 · Cited by 6 · see citing works
- 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.
- ORCID
- Venue
- Nature
- Published
- 2021-01-06
- Volume
- 590
- Issue
- 7846
- Pages
- 473-479
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8039910
- 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
- green
- www.zora.uzh.ch
- Licence
- 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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