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

Abstract

Cellular metabolism plays an important role in regulating both human and murine NK cell functions. However, it remains unclear whether cellular metabolic process impacts on the function of decidual NK cells (dNK), essential tissue-resident immune cells maintaining the homeostasis of maternal-fetal interface. Remarkably, we found that glycolysis blockage enhances dNK VEGF-A production but restrains its proliferation. Furthermore, levels of IFN-γ and TNF-α secreted by dNK get decreased when glycolysis or oxidative phosphorylation (OXPHOS) is inhibited. Additionally, glycolysis, OXPHOS, and fatty acid oxidation disruption has little effects on the secretion and the CD107a-dependent degranulation of dNK. Mechanistically, we discovered that the mammalian target of rapamycin complex 1 (mTORC1) signaling inhibition leads to decreased glycolysis and OXPHOS in dNK. These limited metabolic processes are associated with attenuated dNK functions, which include restricted production of cytokines including IFN-γ and TNF-α, diminished CD107a-dependent degranulation, and restrained dNK proliferation. Finally, we reported that the protein levels of several glycolysis-associated enzymes are altered and the mTORC1 activity is significantly lower in the decidua of women with recurrent pregnancy loss (RPL) compared with normal pregnancy, which might give new insights about the pathogenesis of RPL. Collectively, our data demonstrate that glucose metabolism and mTORC1 signaling support dNK functions in early pregnancy.

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

“…In accordance, this subtype contained more cytoplasmic granules and expressed higher levels of PRF1, GNLY, GZMA, and GZMB 24 . A recent study demonstrated that glycolysis inhibition restrained the proliferation of dNK cells, production of IFN‐γ and tumor necrosis factor‐α (TNF‐α), but upregulated the secretion of VEGF‐A, indicating the regulatory roles of glycolysis in the functions of dNK cells 40 . The activation of mTOR in dNK cells might also be induced by IL‐15 since it was strongly expressed by DSCs and epithelial cells during the secretory phase and pregnancy following the priming of progesterone 41,42 .…”

“…24 A recent study demonstrated that glycolysis inhibition restrained the proliferation of dNK cells, production of IFNγ and tumor necrosis factorα (TNFα), but upregulated the secretion of VEGF-A, indicating the regulatory roles of glycolysis in the functions of dNK cells. 40 The activation of mTOR in dNK cells might also be induced by IL-15 since it was strongly expressed by DSCs and epithelial cells during the secretory phase and pregnancy following the priming of progesterone. 41,42 However, it seems the glucose-driven metabolic pathway is critical for the functions of both cytotoxic and regulatory NK cells.…”

Glycolysis: A fork in the path of normal and pathological pregnancy

“…The activity of mTORC1 was also decreased in the decidua of patients with RPL 109 . Based on the fact that Rapa‐induce mTORC1 inhibition affected dNK proliferation, metabolism, and function, Yan et al.…”

“…Therefore, the different conditions and undefined cell subtypes used in the two aforementioned studies may account for the discrepancies in their conclusions. In terms of regulatory mechanisms, the inhibition of mTORC1 reduced both glycolysis and OXPHOS in dNK, thereby limiting dNK proliferation and the production of cytokines, such as IFN‐γ and TNF‐α 109 . HLA‐E mediated by extracellular vesicles derived from trophoblasts can also promote dNK glycolysis via mTORC1 111 .…”

“…132 In addition, both PKM2 and LDHA were downregulated in the decidua of patients with RPL compared with that in normal controls. 97,109 A recent proteomic analysis disclosed mitochondrial oxidative stress disorder in the decidua of RPL. 133 However, another investigation failed to detect any significant difference in metabolite concentration between the decidua of individuals with RPL and the controls.…”