title: Deficient tryptophan catabolism along the kynurenine pathway reveals that the epididymis is in a unique tolerogenic state.
abstract: Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway. Intriguingly, IDO is constitutively and highly expressed in the mammalian epididymis in contrast to most other tissues where IDO is induced by proinflammatory cytokines, such as interferons. To gain insight into the role of IDO in the physiology of the mammalian epididymis, we studied both wild type and Ido1(-/-)-deficient mice. In the caput epididymis of Ido1(-/-) animals, the lack of IDO activity was not compensated by other tryptophan-catabolizing enzymes and led to the loss of kynurenine production. The absence of IDO generated an inflammatory state in the caput epididymis as revealed by an increased accumulation of various inflammation markers. The absence of IDO also increased the tryptophan content of the caput epididymis and generated a parallel increase in caput epididymal protein content as a consequence of deficient proteasomal activity. Surprisingly, the lack of IDO expression had no noticeable impact on overall male fertility but did induce highly significant increases in both the number and the percentage of abnormal spermatozoa. These changes coincided with a significant decrease in white blood cell count in epididymal fluid compared with wild type mice. These data provide support for IDO playing a hitherto unsuspected role in sperm quality control in the epididymis involving the ubiquitination of defective spermatozoa and their subsequent removal.
authors.affiliation: From the GReD, CNRS UMR 6247/INSERM U931, Clermont Université, 24 Avenue des Landais, BP 80026, 63171 Aubière Cedex, France.
authors.forename: Aicha
authors.initials: A
authors.lastname: Jrad-Lamine
authors.affiliation: From the GReD, CNRS UMR 6247/INSERM U931, Clermont Université, 24 Avenue des Landais, BP 80026, 63171 Aubière Cedex, France.
authors.forename: Joelle
authors.initials: J
authors.lastname: Henry-Berger
authors.affiliation: Institut National de Le Recherche Agronomique-Biopolymères, Interactions, Assemblages, 44316 Nantes Cedex, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Gourbeyre
authors.affiliation: From the GReD, CNRS UMR 6247/INSERM U931, Clermont Université, 24 Avenue des Landais, BP 80026, 63171 Aubière Cedex, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Damon-Soubeyrand
authors.affiliation: From the GReD, CNRS UMR 6247/INSERM U931, Clermont Université, 24 Avenue des Landais, BP 80026, 63171 Aubière Cedex, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Lenoir
authors.affiliation: Institut National de Le Recherche Agronomique, UMR 1019, UNH, CRNH Auvergne and Clermont Université, Unité de Nutrition Humaine, BP10448, F-63000 Clermont-Ferrand, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Combaret
authors.affiliation: From the GReD, CNRS UMR 6247/INSERM U931, Clermont Université, 24 Avenue des Landais, BP 80026, 63171 Aubière Cedex, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Saez
authors.affiliation: From the GReD, CNRS UMR 6247/INSERM U931, Clermont Université, 24 Avenue des Landais, BP 80026, 63171 Aubière Cedex, France.
authors.forename: Ayhan
authors.initials: A
authors.lastname: Kocer
authors.affiliation: Department of Biochemistry, Kawasaki Medical School, Okayama 701-0192, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Tone
authors.affiliation: Division of Biological Chemistry, Biocentre, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fuchs
authors.affiliation: the Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhu
authors.affiliation: the Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.affiliation: the Immunotherapy Center and; Departments of Pediatrics and.
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.affiliation: the Immunotherapy Center and; Medicine, Medical College of Georgia, Augusta, Georgia 30912.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.affiliation: Faculté des Sciences de Tunis, Département de Biologie, Université de Tunis El Manar, Mutuelleville, 1060 Tunis, Tunesia, and.
authors.forename: Najoua
authors.initials: N
authors.lastname: Gharbi
authors.affiliation: From the GReD, CNRS UMR 6247/INSERM U931, Clermont Université, 24 Avenue des Landais, BP 80026, 63171 Aubière Cedex, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Cadet
authors.affiliation: the Australian Research Council Centre of Excellence in Biotechnology and Development, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: R John
authors.initials: RJ
authors.lastname: Aitken
authors.affiliation: From the GReD, CNRS UMR 6247/INSERM U931, Clermont Université, 24 Avenue des Landais, BP 80026, 63171 Aubière Cedex, France,. Electronic address: joel.drevet@univ-bpclermont.fr.
authors.forename: Joël R
authors.initials: JR
authors.lastname: Drevet
mesh_terms: D000818:Animals; D004822:Epididymis / Q000201:enzymology* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007248:Infertility, Male / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007737:Kynurenine / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009928:Organ Specificity; D013094:Spermatozoa / Q000201:enzymology* / Q000473:pathology; D014364:Tryptophan / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014364:Tryptophan