title: 1-Methyl-tryptophan attenuates regulatory T cells differentiation due to the inhibition of estrogen-IDO1-MRC2 axis in endometriosis.
abstract: Foxp3+regulatory T (Treg) cells contribute to the local dysfunctional immune environment in endometriosis, an estrogen-dependent gynecological disease, which affects the function of ectopic endometrial tissue clearance by the immune system. The reason for the high percentage of peritoneal Tregin endometriosis patients is unknown. Here, we show that the proportion of peritoneal Tregcells increases as endometriosis progresses. To determine the probable mechanism, we established a naive T cell-macrophage-endometrial stromal cell (ESC) co-culture system to mimic the peritoneal cavity microenvironment. After adding 1-methyl-tryptophan (1-MT), a specific inhibitor of indoleamine 2,3-dioxygenase-1 (IDO1), to the co-culture system, we found that the differentiation of Tregcells, mainly IL-10+Tregcells, decreased. Therefore, 1-MT-pretreated ESCs-educated Tregcells performed impaired suppressive function. Moreover, estrogen promoted the differentiation of Tregcells by elevating IDO1 expression in the ectopic lesion. Subsequently, we examined mannose receptor C, type 2 (MRC2), which is an up-stream molecule of IL-10, by bioinformatics analysis and real-time PCR validation. MRC2 expression in ectopic ESCs was notably lower than that in normal ESCs, which further negatively regulated the expression of IDO1 and Ki-67 in ESCs. Furthermore, MRC2 is required for Tregdifferentiation in the ectopic lesion, especially that for CD4highTreg. Therefore, MRC2-silenced ESCs-educated Tregmanifested a stronger suppressive function in vitro. Consistently, the percentage of Tregincreased when MRC2-shRNA was administered in the peritoneal cavity of endometriosis-disease mice model. Besides, 1-MT improved the condition of endometriosis, in terms of reducing the number and weight of total ectopic lesions in vivo. These results indicate that the estrogen-IDO1-MRC2 axis participates in the differentiation and function of Tregand is involved in the development of endometriosis. Thus, blockage of IDO1 in the ectopic lesion, which does not influence physiological functions of estrogen, may be considered a potential therapy for endometriosis.
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wei
authors.affiliation: Reproductive Medicine Center, Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medicine School, Nanjing 210000, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Mei
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, China.
authors.forename: Lingli
authors.initials: L
authors.lastname: Tang
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, China.
authors.forename: Yukai
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, China.
authors.forename: Dajin
authors.initials: D
authors.lastname: Li
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, China.
authors.forename: Mingqing
authors.initials: M
authors.lastname: Li
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, China.|Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Zhu
mesh_terms: D000328:Adult; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D018450:Disease Progression; D004715:Endometriosis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism*; D018655:Lymphocyte Count; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010537:Peritoneum / Q000187:drug effects / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000473:pathology*; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
chemical_list: D004967:Estrogens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D014364:Tryptophan; C525396:1-methyltryptophan