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.
Highlights
Decidual natural killer cells represent the largest population of decidua-resident immune cells, comprising about 50–70% of the maternal immune cells across early pregnancy [1]
Considering mammalian target of rapamycin complex 1 (mTORC1) regulates decidual NK cells (dNK) functions and this effect is dependent on cellular metabolism, we investigated if glycolysis and mTORC1 activity is altered in the recurrent pregnancy loss (RPL) decidua
This study found that dNK metabolic process underpinned dNK functions: glycolysis blockage would enhance dNK vascular endothelial growth factor (VEGF)-A production while restraining cellular proliferation
Summary
Decidual natural killer cells (dNK) represent the largest population of decidua-resident immune cells, comprising about 50–70% of the maternal immune cells across early pregnancy [1]. Studies have revealed that dNK are phenotypically and functionally distinct from peripheral NK cells (pNK) and exert multiple functions to maintain homeostasis of the decidual microenvironment. DNK can directly promote vascular angiogenesis by producing vascular endothelial growth factor (VEGF) and placental growth factor (PLGF) [2, 3]. IFN-g produced by dNK is involved in promoting spiral artery remodeling [4] and inhibiting inflammatory T helper 17 (TH17) cells. Metabolic Requirements for dNK Functions response to maintain immune tolerance [4]. DNK can acquire cytotoxic abilities when infection occurs [5–7]. Previous studies indicated that dNK in the former disorders showed altered cytokines/chemokines and growth factor producing abilities, such as VEGF-A, IFN-g, TNF-a, pleiotrophin, and osteoglycin [8, 10, 11]. The underlying mechanisms determining dNK function under physiological and pathological conditions remain to be elucidated
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