The crosstalk between endometrial stromal cells and macrophages impairs cytotoxicity of NK cells in endometriosis by secreting IL-10 and TGF-β

Abstract

The dysfunction of NK cells in women with endometriosis (EMS) contributes to the immune escape of menstrual endometrial fragments refluxed into the peritoneal cavity. The reciprocal communications between endometrial stromal cells (ESCs) and lymphocytes facilitate the development of EMS. However, the mechanism of these communications on cytotoxicity of natural killer (NK) cells in endometriotic milieus is still largely unknown. To imitate the local immune microenvironment, the co-culture systems of ESCs from patients with EMS and monocyte-derived macrophages or of ESCs, macrophages and NK cells were constructed. The cytokine levels in the co-culture unit were evaluated by ELISA. The expression of functional molecules in NK cells was detected by flow cytometry (FCM). The NK cell behaviors were analyzed by cell counting kit-8 and cytotoxic activation assays. After incubation with ESCs and macrophages, the expression of CD16, NKG2D, perforin and IFN-γ, viability and cytotoxicity of NK cells were significantly downregulated. The secretion of interleukin (IL)-1β, IL-10 and transforming growth factor (TGF)-β in the co-culture system of ESCs and macrophages was increased. Exposure with anti-IL-10 receptor β neutralizing antibody (αhIL-10Rβ) or αTGF-β could partly reverse these effects of ESCs and macrophages on NK cells These results suggest that the interaction between macrophages and ESCs downregulates cytotoxicity of NK cells possibly by stimulating the secretion of IL-10 and TGF-β, and may further trigger the immune escape of ectopic fragments and promote the occurrence and the development of EMS.

Increased natural killer cell subsets with inhibitory cytokines and inhibitory surface receptors in patients with recurrent miscarriage and decreased or normal subsets in kidney transplant recipients late post-transplant

“…However, there is increasing evidence for immunoregulatory NK cells that might mediate immune responses by secretion of interleukin (IL)-10, IL-4 and transforming growth factor (TGF)-b and/or might be responsive to these particular cytokines [2][3][4][5]. In a co-culture system, the interaction between macrophages and endometrial stromal cells was shown to down-regulate cytotoxicity of NK cells, possibly by stimulating the secretion of IL-10 and TGF-b [6]. In a co-culture system, the interaction between macrophages and endometrial stromal cells was shown to down-regulate cytotoxicity of NK cells, possibly by stimulating the secretion of IL-10 and TGF-b [6].…”

“…A robust reconstitution of immunoregulatory NK cells by day 14 after allogeneic stem cell transplantation is an important determinant of clinical outcome, and it has been suggested that NK cells may suppress the development of the T cell-mediated alloreactive immune response through production of IL-10 [4]. In a co-culture system, the interaction between macrophages and endometrial stromal cells was shown to down-regulate cytotoxicity of NK cells, possibly by stimulating the secretion of IL-10 and TGF-b [6]. Recent evidence provides support for the notion that natural killer T (NK T) cells (a small but important immunoregulatory T cell subset of human peripheral blood lymphocytes) play a pivotal role in pregnancy [7].…”

Indoleamine 2,3-dioxygenase suppresses the cytotoxicity of 1 NK cells in response to ectopic endometrial stromal cells in endometriosis

“…TGF-β plays a key role in decreasing immune cells activity and promoting the implantation, growth and angiogenesis of endometrial tissue in the peritoneal cavity (Hull et al 2012). Although a high level of TGF-β is reported in the serum, PF and ectopic endometrium of women with EMS (Oosterlynck et al 1994, Pizzo et al 2002, Young et al 2014, our recent study confirmed that TGF-β could impair the cytotoxicity of NK cells (Yang et al 2017). In addition, it was reported that IDO expression is negatively correlated with the suppressor of cytokine signaling 3 (SOCS3) and positively correlated with TGF-β (Liu et al 2017).…”

“…However, there are no treatments thus far due to the controversial pathogenesis of the disease. Despite anatomical, genetic, endocrine, environmental and dietary factors (Simpson et al 1980, Missmer et al 2004, Bulun 2009, Vannuccini et al 2016, accumulating evidence have showed that an aberrant immune microenvironment in the abdominal cavity plays a significant role in the initiation and progression of EMS by preventing retrograde menstruation from immune clearance, as well as allowing the attachment, implantation and angiogenesis of endometrial cells (Matarese et al 2003, Jeung et al 2016, Yu et al 2016, Yang et al 2017.…”

“…Specifically, reductions in NK cell cytotoxicity, such as low levels of granzyme B, perforin, TRAIL and CD107a, were observed in the PF of patients with EMS (Oosterlynck et al 1991, Funamizu et al 2014. Our previous study had revealed that crosstalk between ESCs and macrophages impairs the cytotoxicity of NK cells by secreting IL-10 and transforming growth factor (TGF)-β in EMS (Yang et al 2017), and ESCs derived IL-15 inhibits the killing activity of NK cells in EMS (Yu et al 2016). That is, cytokines change the endometrial milieu in the peritoneal cavity of patients with EMS and thus diminish the cytotoxic activity of NK cells, although the detailed intracellular mechanisms for NK cells remain unknown.…”