Role of indoleamine 2,3-dioxygenase in testicular immune-privilege

GUALDONI, GISELA S.; JACOBO, PATRICIA V.; SOBARZO, CRISTIAN M.; PÉREZ, CECILIA V.; MATZKIN, MARÍA E.; HÖCHT, CHRISTIAN; FRUNGIERI, MÓNICA B.; HILL, MARCELO; ANEGON, IGNACIO; LUSTIG, LIVIA; GUAZZONE, VANESA A.

Scientific Reports

Nature

Año: 2019 vol. 9

2045-2322

Male meiotic germ cell including the spermatozoa represent a great challenge to the immune system,as they appear long after the establishment of normal immune tolerance mechanisms. The capacity ofthe testes to tolerate autoantigenic germ cells as well as survival of allogeneic organ engrafted in thetesticular interstitium have led to consider the testis an immunologically privileged site. Disruptionof this immune privilege following trauma, tumor, or autoimmune orchitis often results in maleinfertility. Strong evidence indicates that indoleamine 2,3-dioxygenase (IDO) has been implicatedin fetal and allograft tolerance, tumor immune resistance, and regulation of autoimmune diseases.IDO and tryptophan 2,3-dioxygenase (TDO) catalyze the same rate-limiting step of tryptophanmetabolism along a common pathway, which leads to tryptophan starvation and generation ofcatabolites collectively known as kynurenines. However, the relevance of tryptophan metabolismin testis pathophysiology has not yet been explored. Here we assessed the in vivo role of IDO/TDOin experimental autoimmune orchitis (EAO), a model of autoimmune testicular infammation andimmunologically impaired spermatogenesis. EAO was induced in adult Wistar rats with testicularhomogenate and adjuvants. Control (C) rats injected with saline and adjuvants and normal untreatedrats (N) were also studied. mRNA expression of IDO decreased in whole testes and in isolated Sertolicells during EAO. TDO and IDO localization and level of expression in the testis were analyzed byimmunostaining and Western blot. TDO is expressed in granulomas from EAO rats, and similar proteinlevels were observed in N, C, and EAO groups. IDO was detected in mononuclear and endothelial cellsand reduced IDO expression was detected in EAO group compared to N and C rats. This phenomenonwas concomitant with a signifcant reduction of IDO activity in EAO testis measured by tryptophan andkynurenine concentrations (HPLC). Finally, in vivo inhibition of IDO with 1-methyl-tryptophan increasedseverity of the disease, demonstrating down regulation of IDO-based tolerance when testicular immuneregulation was disrupted. We present evidence that an IDO-based mechanism is involved in testicularimmune privilege.