Deficient tryptophan catabolism along the kynurenine pathway reveals that the epididymis is in a unique tolerogenic state

Aicha Jrad-Lamine, Joelle Henry-Berger, Pascal Gourbeyre, Christelle Damon-Soubeyrand, Alain Lenoir, Lydie Combaret, Fabrice Saez, Ayhan Kocer, Shigenobu Tone, Dietmar Fuchs, Wentao Zhu, Peter J. Oefner, David H. Munn, Andrew L. Mellor, Najoua Gharbi, Rémi Cadet, R. John Aitken, Joël R. Dreveta

Research output: Contribution to journalArticle

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8030-8042
Number of pages13
JournalJournal of Biological Chemistry
Volume286
Issue number10
DOIs
StatePublished - Mar 11 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Jrad-Lamine, A., Henry-Berger, J., Gourbeyre, P., Damon-Soubeyrand, C., Lenoir, A., Combaret, L., Saez, F., Kocer, A., Tone, S., Fuchs, D., Zhu, W., Oefner, P. J., Munn, D. H., Mellor, A. L., Gharbi, N., Cadet, R., Aitken, R. J., & Dreveta, J. R. (2011). Deficient tryptophan catabolism along the kynurenine pathway reveals that the epididymis is in a unique tolerogenic state. Journal of Biological Chemistry, 286(10), 8030-8042. https://doi.org/10.1074/jbc.M110.172114