Cited by 1,559Tryptophan and brain disordersinterferon and immune responsesMultiple Sclerosis Research Studies

Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor

Open access
Rothhammer, Veit, Mascanfroni, Ivan D, Bunse, Lukas, Takenaka, Maisa C, Kenison, Jessica E, Mayo, Lior, Chao, Chun-Cheih, Patel, Bonny +14 more·2016·Nature Medicine

Abstract

Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-β are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/nm.4106

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Rothhammer, V., Mascanfroni, I. D., Bunse, L., Takenaka, M. C., Kenison, J. E., Mayo, L., Chao, C.-C., Patel, B., Yan, R., Blain, M., Alvarez, J. I., Kébir, H., Anandasabapathy, N., Izquierdo, G., Jung, S., Obholzer, N., Pochet, N., Clish, C. B., Prinz, M., Prat, A., Antel, J., & Quintana, F. J.
Affiliations
  • Brigham and Women's Hospital (US)
  • Montreal Neurological Institute and Hospital (CA)
  • University of Pennsylvania (US)
  • Centre Hospitalier de l’Université de Montréal (CA)
  • Universidad de Sevilla (ES)
  • Weizmann Institute of Science (IL)
  • Broad Institute (US)
  • University of Freiburg (DE)
Corresponding author
Quintana, Francisco J
Venue
Nature Medicine
Published
2016-05-09
Volume
22
Issue
6
Pages
586-597
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
OpenAlex
W2345604850
Cited by
1,559
References
65
Citations by year
2026: 168 · 2025: 190 · 2024: 192 · 2023: 208 · 2022: 200 · 2021: 164 · 2020: 147 · 2019: 104 · 2018: 96 · 2017: 68 · 2016: 20
FWCI
32.89
Type
journal article
Language
en
Open access
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders
National Institute of Allergy and Infectious Diseases (R00AI075285, K99AI075285, R01AI093903, R56AI093903, R01AI126880)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
type I interferon, aryl hydrocarbon receptor, astrocytes, neuroinflammation, multiple sclerosis, experimental autoimmune encephalomyelitis, tryptophan metabolites, gut microbiota, SOCS2, interferon-beta, indole-3-propionic acid, indole-3-carboxaldehyde, tryptophanase, dietary tryptophan, central nervous system autoimmunity
MeSH terms
Gastrointestinal Microbiome, Animals, Astrocytes, Central Nervous System, Chromatography, High Pressure Liquid, Encephalomyelitis, Autoimmune, Experimental, Fluorescent Antibody Technique, Glial Fibrillary Acidic Protein, Humans, Indican, Indoles, Inflammation, Interferon Type I, Multiple Sclerosis, Serotonin, T-Lymphocytes, Tryptophan, Tryptophanase, Immunoblotting, Case-Control Studies, Polymerase Chain Reaction, Interferon-beta, Receptors, Aryl Hydrocarbon, Mice, Knockout, Chemokine CCL2, Gene Expression Profiling, Chromatin Immunoprecipitation, Cell Proliferation, STAT1 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice, Limosilactobacillus reuteri, Nitric Oxide Synthase Type II, Receptor, Interferon alpha-beta, Gene Knockdown Techniques, Optical Imaging, Myxovirus Resistance Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review