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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

Nature Medicine volume 22, pages 586–597 (2016)Cite this article

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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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References

  1. Allen, N.J. et al. Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature 486, 410–414 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Alvarez, J.I. et al. The Hedgehog pathway promotes blood–brain barrier integrity and CNS immune quiescence. Science 334, 1727–1731 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Chung, W.S. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504, 394–400 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Khakh, B.S. & Sofroniew, M.V. Diversity of astrocyte functions and phenotypes in neural circuits. Nat. Neurosci. 18, 942–952 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Molofsky, A.V. et al. Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. Nature 509, 189–194 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Obermeier, B., Daneman, R. & Ransohoff, R.M. Development, maintenance and disruption of the blood–brain barrier. Nat. Med. 19, 1584–1596 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rieckmann, P. & Engelhardt, B. Building up the blood–brain barrier. Nat. Med. 9, 828–829 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Sofroniew, M.V. Astrocyte barriers to neurotoxic inflammation. Nat. Rev. Neurosci. 16, 249–263 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tsai, H.H. et al. Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337, 358–362 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lassmann, H. Mechanisms of white matter damage in multiple sclerosis. Glia 62, 1816–1830 (2014).

    Article  PubMed  Google Scholar 

  11. Mayo, L. et al. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat. Med. 20, 1147–1156 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shao, W. et al. Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin. Nature 494, 90–94 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Smith, P.M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Baruch, K. et al. Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346, 89–93 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ivashkiv, L.B. & Donlin, L.T. Regulation of type I interferon responses. Nat. Rev. Immunol. 14, 36–49 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sandler, N.G. et al. Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression. Nature 511, 601–605 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yan, Y. et al. CNS-specific therapy for ongoing EAE by silencing IL-17 pathway in astrocytes. Mol. Ther. 20, 1338–1348 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Quintana, F.J. & Sherr, D.H. Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol. Rev. 65, 1148–1161 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Stockinger, B., Di Meglio, P., Gialitakis, M. & Duarte, J.H. The aryl hydrocarbon receptor: multitasking in the immune system. Annu. Rev. Immunol. 32, 403–432 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Prinz, M. et al. Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 28, 675–686 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Fitzgerald, D.C. et al. Suppressive effect of IL-27 on encephalitogenic TH17 cells and the effector phase of experimental autoimmune encephalomyelitis. J. Immunol. 179, 3268–3275 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Mitsdoerffer, M. & Kuchroo, V. New pieces in the puzzle: how does interferon-β really work in multiple sclerosis? Ann. Neurol. 65, 487–488 (2009).

    Article  PubMed  Google Scholar 

  25. Mascanfroni, I.D. et al. Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α. Nat. Med. 21, 638–646 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mascanfroni, I.D. et al. IL-27 acts on DCs to suppress the T cell response and autoimmunity by inducing expression of the immunoregulatory molecule CD39. Nat. Immunol. 14, 1054–1063 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Apetoh, L. et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat. Immunol. 11, 854–861 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yeste, A., Nadeau, M., Burns, E.J., Weiner, H.L. & Quintana, F.J. Nanoparticle-mediated co-delivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 109, 11270–11275 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Weidemann, A. et al. The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice. J. Clin. Invest. 119, 3373–3383 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Jessen, K.R. & Mirsky, R. Glial cells in the enteric nervous system contain glial fibrillary acidic protein. Nature 286, 736–737 (1980).

    Article  CAS  PubMed  Google Scholar 

  31. Kim, R.Y. et al. Astrocyte CCL2 sustains immune cell infiltration in chronic experimental autoimmune encephalomyelitis. J. Neuroimmunol. 274, 53–61 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mc Guire, C., Prinz, M., Beyaert, R. & van Loo, G. Nuclear factor kappa B (NF-κB) in multiple sclerosis pathology. Trends Mol. Med. 19, 604–613 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. van Loo, G. et al. Inhibition of transcription factor NF-κB in the central nervous system ameliorates autoimmune encephalomyelitis in mice. Nat. Immunol. 7, 954–961 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Boverhof, D.R. et al. 2,3,7,8-tetrachlorodibenzo-p-dioxin induces suppressor of cytokine signaling 2 in murine B cells. Mol. Pharmacol. 66, 1662–1670 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Zadjali, F. et al. Socs2 deletion protects against hepatic steatosis but worsens insulin resistance in high-fat-diet-fed mice. FASEB J. 26, 3282–3291 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. Axtell, R.C. et al. T helper type 1 and 17 cells determine efficacy of interferon-β in multiple sclerosis and experimental encephalomyelitis. Nat. Med. 16, 406–412 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Borden, E.C. et al. Interferons at age 50: past, current and future impact on biomedicine. Nat. Rev. Drug Discov. 6, 975–990 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ross, T.M. et al. Intranasal administration of interferon-β bypasses the blood–brain barrier to target the central nervous system and cervical lymph nodes: a non-invasive treatment strategy for multiple sclerosis. J. Neuroimmunol. 151, 66–77 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Farez, M.F. et al. Melatonin contributes to the seasonality of multiple sclerosis relapses. Cell 162, 1338–1352 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gandhi, R. et al. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell–like and Foxp3+ regulatory T cells. Nat. Immunol. 11, 846–853 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Wikoff, W.R. et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl. Acad. Sci. USA 106, 3698–3703 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Schroeder, J.C. et al. The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry 49, 393–400 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Palace, J., Leite, M.I., Nairne, A. & Vincent, A. Interferon-β treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers. Arch. Neurol. 67, 1016–1017 (2010).

    Article  PubMed  Google Scholar 

  47. Khorooshi, R. et al. Induction of endogenous type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis. Acta Neuropathol. 130, 107–118 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dann, A. et al. Cytosolic RIG-I-like helicases act as negative regulators of sterile inflammation in the CNS. Nat. Neurosci. 15, 98–106 (2012).

    Article  CAS  Google Scholar 

  49. Ejlerskov, P. et al. Lack of neuronal IFN-β–IFNAR causes Lewy body– and Parkinson's disease–like dementia. Cell 163, 324–339 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Goldmann, T. et al. USP18 lack in microglia causes destructive interferonopathy of the mouse brain. EMBO J. 34, 1612–1629 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Quintana, F.J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Quintana, F.J. et al. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 107, 20768–20773 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17 cell–mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Bessede, A. et al. Aryl hydrocarbon receptor control of a disease tolerance defense pathway. Nature 511, 184–190 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Opitz, C.A. et al. An endogenous tumor-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Monteleone, I. et al. Aryl-hydrocarbon-receptor-induced signals upregulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141, 237–248, 248.e1 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Atarashi, K. et al. TH17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163, 367–380 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lee, Y.K., Menezes, J.S., Umesaki, Y. & Mazmanian, S.K. Proinflammatory T cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 108, 4615–4622 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Ochoa-Repáraz, J. et al. Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J. Immunol. 185, 4101–4108 (2010).

    Article  PubMed  CAS  Google Scholar 

  60. Viaud, S. et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971–976 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Prinz, M., Priller, J., Sisodia, S.S. & Ransohoff, R.M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14, 1227–1235 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. Trapnell, C. et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat. Protoc. 7, 562–578 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Jack, C.S. et al. TLR signaling tailors innate immune responses in human microglia and astrocytes. J. Immunol. 175, 4320–4330 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Alvarez, J.I. et al. Focal disturbances in the blood–brain barrier are associated with formation of neuroinflammatory lesions. Neurobiol. Dis. 74, 14–24 (2015).

    Article  CAS  PubMed  Google Scholar 

  65. Townsend, M.K. et al. Reproducibility of metabolomic profiles among men and women in two large cohort studies. Clin. Chem. 59, 1657–1667 (2013).

    Article  CAS  PubMed  Google Scholar 

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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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Authors and Affiliations

  1. Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Veit Rothhammer, Ivan D Mascanfroni, Lukas Bunse, Maisa C Takenaka, Jessica E Kenison, Lior Mayo, Chun-Cheih Chao, Bonny Patel, Raymond Yan, Nikolaus Obholzer, Nathalie Pochet & Francisco J Quintana

  2. Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

    Manon Blain & Jack Antel

  3. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Jorge I Alvarez

  4. Neuroimmunology Research Lab, Center for Excellence in Neuromics CRCHUM, Université de Montréal, Montréal, Quebec, Canada

    Hania Kébir & Alexandre Prat

  5. Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Niroshana Anandasabapathy

  6. Molecular Biology Service, University of Sevilla, Sevilla, Spain

    Guillermo Izquierdo

  7. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

    Steffen Jung

  8. Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA

    Nikolaus Obholzer & Nathalie Pochet

  9. Metabolite Profiling Platform, Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA

    Clary B Clish

  10. Institute of Neuropathology, University of Freiburg, Freiburg, Germany

    Marco Prinz

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  1. Veit Rothhammer
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Contributions

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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