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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.

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Figure 1: CNS inflammation induces a type I IFN signature in astrocytes.
Figure 2: Type I IFN signaling in astrocytes limits CNS inflammation.
Figure 3: IFN-β induces Ahr expression in astrocytes.
Figure 4: AHR in astrocytes limits CNS inflammation.
Figure 5: Microbial metabolites of tryptophan and IFN-β suppress CNS inflammation via AHR in astrocytes.
Figure 6: Human astrocyte activation is controlled by IFN-β and AHR signaling.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH) grants AI075285 (F.J.Q.) and AI093903 (F.J.Q.), the National Multiple Sclerosis Society grant RG4111A1 (F.J.Q.), the International Progressive MS Alliance grants PA0069 (F.J.Q.) and PA-1501-02847 (F.J.Q.), an educational grant from Mallinckrodt Pharmaceuticals (A219074; V.R.), a fellowship from the German Research Foundation (DFG RO4866 1/1; V.R.), postdoctoral fellowships from the National Multiple Sclerosis Society (FG 2036-A1/1 (I.D.M) and FG1941A1/2 (L.M.)), a fellowship from the International Academy of Life Sciences (L.B.), a postdoctoral Research Abroad Program award from the Ministry of Science and Technology, Taiwan (104-2917-I-564 -024; C.-C.C.) and a fellowship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil (BEX 0571/15-6; M.C.T.). Cx3cr1-CreERT2 mice were a kind gift from S. Jung (Weizmann Institute of science). The pLenti-Gfap-eGFP-mir30-shAct1 vector was a gift from G.-X. Zhang.

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V.R., I.D.M., L.B., M.C.T., J.E.K., L.M., C.-C.C., H.K., J.I.A., M.B. and C.B.C. performed in vitro and in vivo experiments; B.P., R.Y., N.O. and N.P. performed bioinformatics analysis; N.A., G.I., C.B.C., A.P., S.J., M.P. and J.A. provided unique reagents, and discussed and/or interpreted findings; V.R. and F.J.Q. wrote the manuscript; and F.J.Q. designed and supervised the study and edited the manuscript.

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Correspondence to Francisco J Quintana.

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Rothhammer, V., Mascanfroni, I., Bunse, L. et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 22, 586–597 (2016). https://doi.org/10.1038/nm.4106

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