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Nat Med. 2016 Jun;22(6):586-97. doi: 10.1038/nm.4106. Epub 2016 May 9.

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

Author information

1
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2
Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
3
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
4
Neuroimmunology Research Lab, Center for Excellence in Neuromics CRCHUM, Université de Montréal, Montréal, Quebec, Canada.
5
Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
6
Molecular Biology Service, University of Sevilla, Sevilla, Spain.
7
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
8
Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA.
9
Metabolite Profiling Platform, Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.
10
Institute of Neuropathology, University of Freiburg, Freiburg, Germany.

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.

PMID:
27158906
PMCID:
PMC4899206
DOI:
10.1038/nm.4106
[Indexed for MEDLINE]
Free PMC Article

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