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

Nature Medicine

Volumn 22, Issue 6, 2016, Pages 586-597

  Rothhammer, Veit ^a   Mascanfroni, Ivan D ^a   Bunse, Lukas ^a   Takenaka, Maisa C ^a   Kenison, Jessica E ^a   Mayo, Lior ^a   Chao, Chun Cheih ^a   Patel, Bonny ^a   Yan, Raymond ^a   Blain, Manon ^b   Alvarez, Jorge I ^c   Kébir, Hania ^d   Anandasabapathy, Niroshana ^a   Izquierdo, Guillermo ^e   Jung, Steffen ^f   Obholzer, Nikolaus ^a,g   Pochet, Nathalie ^a,g   Clish, Clary B ^h   Prinz, Marco ⁱ   Prat, Alexandre ^d   Antel, Jack ^b   Quintana, Francisco J ^a   more..

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b MCGILL UNIVERSITY   (Canada)

^c UNIVERSITY OF PENNSYLVANIA   (United States)

^d UNIVERSITY OF MONTREAL   (Canada)

^e UNIVERSITY OF SEVILLE   (Spain)

^f WEIZMANN INSTITUTE OF SCIENCE   (Israel)

^g MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^h BROAD INSTITUTE OF MIT AND HARVARD   (United States)

ⁱ UNIVERSITY OF FREIBURG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

AMPICILLIN; AROMATIC HYDROCARBON RECEPTOR; BETA INTERFERON; INDOLE; INDOLE 3 ALDEHYDE; INDOLEPROPIONIC ACID; INDOXYL 3 SULFATE; INTERFERON; SUPPRESSOR OF CYTOKINE SIGNALING 2; TRYPTOPHAN; TRYPTOPHANASE; UNCLASSIFIED DRUG; ALPHA BETA INTERFERON RECEPTOR; CCL2 PROTEIN, HUMAN; GLIAL FIBRILLARY ACIDIC PROTEIN; IFNAR1 PROTEIN, MOUSE; INDICAN; INDOLE DERIVATIVE; INDOLE-3-CARBALDEHYDE; INDUCIBLE NITRIC OXIDE SYNTHASE; MONOCYTE CHEMOTACTIC PROTEIN 1; MX1 PROTEIN, HUMAN; MYXOVIRUS RESISTANCE PROTEIN; NOS2 PROTEIN, HUMAN; SEROTONIN; SOCS2 PROTEIN, MOUSE; STAT1 PROTEIN; STAT1 PROTEIN, HUMAN; SUPPRESSOR OF CYTOKINE SIGNALING;

ANIMAL CELL; ANIMAL EXPERIMENT; ANTIINFLAMMATORY ACTIVITY; ARTICLE; ASTROCYTE; CELL ACTIVITY; CENTRAL NERVOUS SYSTEM; CONTROLLED STUDY; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; GENETIC TRANSCRIPTION; GENOME-WIDE ASSOCIATION STUDY; HUMAN; HUMAN CELL; MOUSE; MULTIPLE SCLEROSIS; NERVOUS SYSTEM INFLAMMATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; ANIMAL; CASE CONTROL STUDY; CELL PROLIFERATION; CHROMATIN IMMUNOPRECIPITATION; FLUORESCENCE IMAGING; FLUORESCENT ANTIBODY TECHNIQUE; GENE EXPRESSION PROFILING; GENE SILENCING; GENETICS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IMMUNOBLOTTING; IMMUNOLOGY; INFLAMMATION; INTESTINE FLORA; KNOCKOUT MOUSE; LACTOBACILLUS REUTERI; METABOLISM; POLYMERASE CHAIN REACTION; T LYMPHOCYTE; URINE;

ANIMALS; ASTROCYTES; CASE-CONTROL STUDIES; CELL PROLIFERATION; CENTRAL NERVOUS SYSTEM; CHEMOKINE CCL2; CHROMATIN IMMUNOPRECIPITATION; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; ENCEPHALOMYELITIS, AUTOIMMUNE, EXPERIMENTAL; FLUORESCENT ANTIBODY TECHNIQUE; GASTROINTESTINAL MICROBIOME; GENE EXPRESSION PROFILING; GENE KNOCKDOWN TECHNIQUES; GLIAL FIBRILLARY ACIDIC PROTEIN; HUMANS; IMMUNOBLOTTING; INDICAN; INDOLES; INFLAMMATION; INTERFERON TYPE I; INTERFERON-BETA; LACTOBACILLUS REUTERI; MICE; MICE, KNOCKOUT; MULTIPLE SCLEROSIS; MYXOVIRUS RESISTANCE PROTEINS; NITRIC OXIDE SYNTHASE TYPE II; OPTICAL IMAGING; POLYMERASE CHAIN REACTION; RECEPTOR, INTERFERON ALPHA-BETA; RECEPTORS, ARYL HYDROCARBON; SEROTONIN; STAT1 TRANSCRIPTION FACTOR; SUPPRESSOR OF CYTOKINE SIGNALING PROTEINS; T-LYMPHOCYTES; TRYPTOPHAN; TRYPTOPHANASE;

EID: 84966658995     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.4106     Document Type: Article

References (65)

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).
2. Alvarez, J.I. et al. The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 334, 1727-1731 (2011).
3. Chung, W.S. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504, 394-400 (2013).
4. Khakh, B.S. & Sofroniew, M.V. Diversity of astrocyte functions and phenotypes in neural circuits. Nat. Neurosci. 18, 942-952 (2015).
5. Molofsky, A.V. et al. Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. Nature 509, 189-194 (2014).
6. Obermeier, B., Daneman, R. & Ransohoff, R.M. Development, maintenance and disruption of the blood-brain barrier. Nat. Med. 19, 1584-1596 (2013).
7. Rieckmann, P. & Engelhardt, B. Building up the blood-brain barrier. Nat. Med. 9, 828-829 (2003).
8. Sofroniew, M.V. Astrocyte barriers to neurotoxic inflammation. Nat. Rev. Neurosci. 16, 249-263 (2015).
9. Tsai, H.H. et al. Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337, 358-362 (2012).
10. Lassmann, H. Mechanisms of white matter damage in multiple sclerosis. Glia 62, 1816-1830 (2014).
11. Mayo, L. et al. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat. Med. 20, 1147-1156 (2014).
12. Shao, W. et al. Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin. Nature 494, 90-94 (2013).
13. Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538-541 (2011).
14. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446-450 (2013).
15. Smith, P.M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569-573 (2013).
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).
17. Ivashkiv, L.B. & Donlin, L.T. Regulation of type I interferon responses. Nat. Rev. Immunol. 14, 36-49 (2014).
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).
19. Yan, Y. et al. CNS-specific therapy for ongoing EAE by silencing IL-17 pathway in astrocytes. Mol. Ther. 20, 1338-1348 (2012).
20. Quintana, F.J. & Sherr, D.H. Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol. Rev. 65, 1148-1161 (2013).
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).
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).
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).
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).
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).
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).
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).
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).
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).
30. Jessen, K.R. & Mirsky, R. Glial cells in the enteric nervous system contain glial fibrillary acidic protein. Nature 286, 736-737 (1980).
31. Kim, R.Y. et al. Astrocyte CCL2 sustains immune cell infiltration in chronic experimental autoimmune encephalomyelitis. J. Neuroimmunol. 274, 53-61 (2014).
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).
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).
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).
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).
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).
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).
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).
39. Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79-91 (2013).
40. Farez, M.F. et al. Melatonin contributes to the seasonality of multiple sclerosis relapses. Cell 162, 1338-1352 (2015).
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).
42. Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629-640 (2011).
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).
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).
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).
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).
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).
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).
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).
50. Goldmann, T. et al. USP18 lack in microglia causes destructive interferonopathy of the mouse brain. EMBO J. 34, 1612-1629 (2015).
51. Quintana, F.J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65-71 (2008).
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).
53. Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17 cell-mediated autoimmunity to environmental toxins. Nature 453, 106-109 (2008).
54. Bessede, A. et al. Aryl hydrocarbon receptor control of a disease tolerance defense pathway. Nature 511, 184-190 (2014).
55. Opitz, C.A. et al. An endogenous tumor-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197-203 (2011).
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).
57. Atarashi, K. et al. TH17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163, 367-380 (2015).
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).
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).
60. Viaud, S. et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971-976 (2013).
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).
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).
63. Jack, C.S. et al. TLR signaling tailors innate immune responses in human microglia and astrocytes. J. Immunol. 175, 4320-4330 (2005).
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).
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).