Extracellular Vesicle-Mediated Secretion of HLA-E by Trophoblasts Maintains Pregnancy by Regulating the Metabolism of Decidual NK Cells

Abstract

Extracellular vesicles derived from trophoblasts (T-EVs) play an important role in pregnancy, but the mechanism is not entirely clear. In this study, we found that HLA-E, which is mostly confined to the cytoplasm of trophoblast cells, was secreted by T-EVs. The level of HLA-E in T-EVs from unexplained recurrent spontaneous abortion (URSA) patients was lower than that in normal pregnancy (NP) and RSA patients who had an abnormal embryo karyotype (AK-RSA). T-EVs promoted secretion of IFN-γ and VEGFα by decidual NK (dNK) cells from URSA patients via HLA-E, VEGFα was necessary for angiogenesis and trophoblast growth, and IFN-γ inhibited Th17 induction. Glycolysis and oxidative phosphorylation (OxPhos) were involved in this process. Glycolysis but not OxPhos of dNK cells facilitated by T-EVs was dependent on mTORC1 activation. Inhibition of T-EV production in vivo increased the susceptibility of mice to embryo absorption, which was reversed by transferring exogenous T-EVs. T-EVs promoted secretion of IFN-γ and VEGFα by dNK cells to maintain pregnancy via Qa-1 in abortion-prone mouse models. This study reveals a new mechanism of pregnancy maintenance mediated by HLA-E via T-EVs.

The metabolic characteristic of decidual immune cells and their unique properties in pregnancy loss*

“…48 Further to this, this in vivo study demonstrated that the inhibition of T-EVs caused more embryo absorption, coupled with a significant reduction in INFγ and VEGFα in dNK cells. 48 As a result, these studies suggested that glucose-driven glycolysis might be required for the activation of dNK cells, but driving forces of glycolysis in the microenvironment might also be involved in the balance between cytotoxic and regulatory functions. However, further studies are still warranted.…”

“…48 As shown in that study, it was also observed that the level of HLA-E in the T-EVs from women with URPL was significantly 6) Maternal obesity leads to a significant reduction in dNK cell numbers but increased TNFα production and impaired uterine artery remodeling or placental development lower than in women with normal pregnancies and pregnancy loss caused by an abnormal embryo karyotype. 48 Further to this, this in vivo study demonstrated that the inhibition of T-EVs caused more embryo absorption, coupled with a significant reduction in INFγ and VEGFα in dNK cells. 48 As a result, these studies suggested that glucose-driven glycolysis might be required for the activation of dNK cells, but driving forces of glycolysis in the microenvironment might also be involved in the balance between cytotoxic and regulatory functions.…”

“…Glycolytic activity and respiration capacity in the dNK cells from URPL subjects were decreased, as well as HLA-E in T-EVs. 48 Intravenous transfer of exogenic mouse T-EVs could ameliorate the embryo resorption rate in the abortion-prone model and facilitate INFγ and VEGFα expression in dNK cells. 48 This protective effect was somewhat decreased when blocking driven glycolysis for treatment and prevention of pregnancy loss.…”

“…48 Intravenous transfer of exogenic mouse T-EVs could ameliorate the embryo resorption rate in the abortion-prone model and facilitate INFγ and VEGFα expression in dNK cells. 48 This protective effect was somewhat decreased when blocking driven glycolysis for treatment and prevention of pregnancy loss. 48 Carbon monoxide (CO) is a product of heme catalyzed by HO-…”

The mTORC1 Signaling Support Cellular Metabolism to Dictate Decidual NK Cells Function in Early Pregnancy

“…Consequently, dNK cellular metabolism and functions are impaired, which might participate in the pathogenesis of RPL. Indeed, recent studies have revealed that glycolysis disturbance occurs at the decidua of RPL, and attenuated ECAR and OCR in RPL dNK compared with healthy controls has also been reported ( 45 , 46 ). In this study, protein levels of HK-II and LDHA were found to be altered, and a decreased mTORC1 activity was observed by Western blot in the RPL decidual samples analyzed.…”