title: Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor.
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.
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Veit
authors.initials: V
authors.lastname: Rothhammer
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Mascanfroni
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lukas
authors.identifier: 0000-0002-4490-7574
authors.initials: L
authors.lastname: Bunse
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Maisa C
authors.initials: MC
authors.lastname: Takenaka
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Kenison
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lior
authors.identifier: 0000-0002-1296-6692
authors.initials: L
authors.lastname: Mayo
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Chun-Cheih
authors.identifier: 0000-0003-4108-2658
authors.initials: CC
authors.lastname: Chao
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Bonny
authors.initials: B
authors.lastname: Patel
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Yan
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Manon
authors.initials: M
authors.lastname: Blain
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Jorge I
authors.initials: JI
authors.lastname: Alvarez
authors.affiliation: Neuroimmunology Research Lab, Center for Excellence in Neuromics CRCHUM, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Hania
authors.initials: H
authors.lastname: Kébir
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Niroshana
authors.initials: N
authors.lastname: Anandasabapathy
authors.affiliation: Molecular Biology Service, University of Sevilla, Sevilla, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Izquierdo
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Obholzer
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pochet
authors.affiliation: Metabolite Profiling Platform, Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Clary B
authors.identifier: 0000-0001-8259-9245
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Neuroimmunology Research Lab, Center for Excellence in Neuromics CRCHUM, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Antel
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Quintana
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D002851:Chromatography, High Pressure Liquid; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D000069196:Gastrointestinal Microbiome; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007200:Indican / Q000652:urine; D007211:Indoles / Q000378:metabolism; D007249:Inflammation; D007370:Interferon Type I / Q000276:immunology*; D016899:Interferon-beta / Q000494:pharmacology; D052200:Limosilactobacillus reuteri; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism; D064547:Myxovirus Resistance Proteins / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D061848:Optical Imaging; D016133:Polymerase Chain Reaction; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000276:immunology* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D012701:Serotonin; D050826:Suppressor of Cytokine Signaling Proteins; D013601:T-Lymphocytes / Q000276:immunology*; D014364:Tryptophan / Q000378:metabolism*; D014368:Tryptophanase / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D005904:Glial Fibrillary Acidic Protein; C508032:Ifnar1 protein, mouse; D007211:Indoles; D007370:Interferon Type I; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D018336:Receptors, Aryl Hydrocarbon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D053633:Receptor, Interferon alpha-beta; D012701:Serotonin; D016899:Interferon-beta; C012381:indole-3-carbaldehyde; C015292:indolepropionic acid; C030374:indole; D014364:Tryptophan; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D014368:Tryptophanase; D007200:Indican