title: Tryptophan-2,3-Dioxygenase (TDO) deficiency is associated with subclinical neuroprotection in a mouse model of multiple sclerosis.
abstract: The catabolism of tryptophan to immunosuppressive and neuroactive kynurenines is a key metabolic pathway regulating immune responses and neurotoxicity. The rate-limiting step is controlled by indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO). IDO is expressed in antigen presenting cells during immune reactions, hepatic TDO regulates blood homeostasis of tryptophan and neuronal TDO influences neurogenesis. While the role of IDO has been described in multiple immunological settings, little is known about TDO's effects on the immune system. TDO-deficiency is neuroprotective in C. elegans and Drosophila by increasing tryptophan and specific kynurenines. Here we have determined the role of TDO in autoimmunity and neurodegeneration in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We created reporter-TDO mice for in vivo imaging to show that hepatic but not CNS TDO expression is activated during EAE. TDO deficiency did not influence myelin-specific T cells, leukocyte infiltration into the CNS, demyelination and disease activity. TDO-deficiency protected from neuronal loss in the spinal cord but not in the optic nerves. While this protection did not translate to an improved overt clinical outcome, our data suggest that spatially distinct neuroprotection is conserved in mammals and support TDO as a potential target for treatment of diseases associated with neurodegeneration.
authors.affiliation: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.|Department of Neurology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
authors.forename: Tobias V
authors.initials: TV
authors.lastname: Lanz
authors.affiliation: AG Neuroinflammation, Department of Neurology, University Hospital Heidelberg, Otto-Meyerhof Zentrum, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Williams
authors.affiliation: AG Neuroinflammation, Department of Neurology, University Hospital Heidelberg, Otto-Meyerhof Zentrum, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Stojic
authors.affiliation: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
authors.forename: Simeon
authors.initials: S
authors.lastname: Iwantscheff
authors.affiliation: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
authors.forename: Jana K
authors.initials: JK
authors.lastname: Sonner
authors.affiliation: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
authors.forename: Carl
authors.initials: C
authors.lastname: Grabitz
authors.affiliation: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Becker
authors.affiliation: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
authors.forename: Laura-Inés
authors.initials: LI
authors.lastname: Böhler
authors.affiliation: AG Brain Tumor Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
authors.forename: Soumya R
authors.initials: SR
authors.lastname: Mohapatra
authors.affiliation: Department of Neuropathology, University Hospital Heidelberg, and Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German cancer Research Center (DKFZ), Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.affiliation: Department of Molecular Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Küblbeck
authors.affiliation: Neurogen Inc., 1-1-52-201 Nakahozumi, Ibaraki 567-0034, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Center for Advanced Research and Education (CARE), Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Funakoshi
authors.affiliation: Department of Neurology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.|AG Brain Tumor Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
authors.forename: Christiane A
authors.initials: CA
authors.lastname: Opitz
authors.affiliation: Department of Neurology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.|DKTK Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Department of Neurology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.|AG Neuroinflammation, Department of Neurology, University Hospital Heidelberg, Otto-Meyerhof Zentrum, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany.
authors.forename: Ricarda
authors.initials: R
authors.lastname: Diem
authors.affiliation: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.|Department of Neurology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.|Department of Neurology, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000473:pathology; D017930:Genes, Reporter; D007249:Inflammation / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008213:Lymphocyte Activation; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D000066829:Neuroprotection; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology; D014366:Tryptophan Oxygenase / Q000172:deficiency* / Q000378:metabolism
chemical_list: D014366:Tryptophan Oxygenase