title: Indoleamine 2,3-dioxygenase-1 (IDO1) in human endometrial stromal cells induces macrophage tolerance through interleukin-33 in the progression of endometriosis.
abstract: In the peritoneal fluid, macrophages and their secretory cytokines are essential for endometriosis, but the factors that favor their involvement in the endometriosis-associated inflammatory response are still elusive. Given the anomalous expression of indoleamine 2,3-dioxygenase-1 (IDO1) in endometrial stromal cells (ESCs) and its potentially important roles in immune modulation, we aimed to determine the effects of IDO1 in ESCs on macrophages and the mechanism of those effects. Normal ESCs and ectopic ESCs transfected with the SD11-IDO1 shRNA (short hairpin RNA) or vector-only plasmid SD11 were subsequently co-cultured with peripheral blood (PB)-derived monocytes (PBMC)-driven macrophages directly and indirectly. Cytokine production was determined by analyzing the supernatant of the co-culture unit by enzyme-linked immunosorbent assay (ELISA). The phenotypes and the phagocytic ability of the macrophages were determined by flow cytometry. Compared to normal ESCs, the PBMC-driven macrophages co-cultured with ectopic ESCs displayed lower phagocytic ability. Additionally, macrophages co-cultured with ectopic ESCs exhibited higher levels of CD163 and CD209 and lower levels of HLA-DR and CD11c. Moreover, both the intracellular expression and extracellular secretion of interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1) were significantly increased, while that of IL-12p70 was decreased in macrophages after being co-cultured with ectopic ESCs. However, there was no significant difference in macrophage phagocytic ability, immunophenotype or cytokine secretion between the direct and indirect co-culture units. Reversely, SD11-IDO1 shRNA transfection of ectopic ESCs could abrogate the decreased phagocytic ability and alternative activation of macrophages in ectopic ESC-macrophage co-culture unit, suggesting that higher IDO1 in ectopic ESCs was indispensable for the induction of macrophage tolerance. Furthermore, the decrease in phagocytic macrophages and alternatively activated macrophages induced by IDO1 in ectopic ESCs was reversed by the addition of an IL-33 inhibitor, that is, soluble ST2 (sST2). Therefore, through the activation of IL-33, the increased expression of IDO1 in ectopic ESCs contributed to the truncated phagocytic ability of macrophages in endometriosis.
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical School, Fudan University Shanghai, 200011, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Mei
authors.affiliation: The Affiliated Jiangyin Hospital of Southeast University Medical College Jiangsu, 214400, China.
authors.forename: Xue-Xin
authors.initials: XX
authors.lastname: Xie
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical School, Fudan University Shanghai, 200011, China.
authors.forename: Ming-Qing
authors.initials: MQ
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: Chun-Yan
authors.initials: CY
authors.lastname: Wei
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical School, Fudan University Shanghai, 200011, China.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Jin
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical School, Fudan University Shanghai, 200011, China.
authors.forename: Da-Jin
authors.initials: DJ
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: Xiao-Yong
authors.initials: XY
authors.lastname: Zhu
mesh_terms: D000328:Adult; D018920:Coculture Techniques; D018450:Disease Progression; D004715:Endometriosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D010587:Phagocytosis / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D055815:Young Adult
chemical_list: C576710:IDO1 protein, human; C506536:IL33 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D000067596:Interleukin-33; D007378:Interleukins
keywords: Endometriosis; cytokine; endometrial stromal cell; indoleamine 2,3-dioxygenase-1; interleukin-33; macrophage