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

• DOI: 10.1038/nm.4106
• Publication Date: 2016-05-09T14:52:21Z
• Authors: Veit Rothhammer; Ivan D Mascanfroni; Lukas Bunse; Maisa C Takenaka; Jessica E Kenison; Lior Mayo; Chun-Cheih Chao; Bonny Patel; Raymond Yan; Manon Blain; Jorge I Alvarez; Hania Kébir; Niroshana Anandas...; Guillermo Izquierdo; Steffen Jung; Nikolaus Obholzer; Nathalie Pochet; Clary B Clish; Marco Prinz; Alexandre Prat; Jack Antel; Francisco J Quintana
• Keywords: Central Nervous System; Chromatin Immunoprecipitation; Encephalomyelitis, Autoimmune, Experimental; Indoles; Immunoblotting; 610; Fluorescent Antibody Technique; 510; 03 medical and health sciences; Glial Fibrillary Acidic Protein; Animals; Humans; Chemokine CCL2; Chromatography, High Pressure Liquid; Cell Proliferation; Inflammation; 0303 health sciences; Gene Expression Profiling; Gastrointestinal Microbiome; 3. Good health; Astrocytes; Case-Control Studies; Gene Knockdown Techniques; Interferon Type I; Indican

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.