The mTORC1 Signaling Support Cellular Metabolism to Dictate Decidual NK Cells Function in Early Pregnancy.
The mTORC1 Signaling Support Cellular Metabolism to Dictate Decidual NK Cells Function in Early Pregnancy.
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mTORC1 信号传导支持细胞代谢，决定妊娠早期蜕膜 NK 细胞的功能
DOI：
10.3389/fimmu.2022.771732
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发表时间：
2022
影响因子：
7.3
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Yan S;Dong J;Qian C;Chen S;Xu Q;Lei H;Wang X
细胞代谢在调节人和小鼠NK细胞功能方面起着重要作用。然而，目前尚不清楚细胞代谢过程是否影响蜕膜NK细胞(DNK)的功能，蜕膜NK细胞是维持母胎界面动态平衡的基本组织驻留免疫细胞。值得注意的是，我们发现糖酵解阻断促进了DNK血管内皮生长因子-A的产生，但抑制了其增殖。此外，当抑制糖酵解或氧化磷酸化(OXPHOS)时，DNK分泌的干扰素-γ和肿瘤坏死因子-α水平下降。此外，糖酵解、OXPHOS和脂肪酸氧化干扰对DNK的分泌和依赖CD107a的脱颗粒几乎没有影响。从机制上，我们发现哺乳动物靶标雷帕霉素复合体1(MTORC1)信号抑制导致DNK糖酵解和OXPHOS减少。这些有限的代谢过程与DNK功能减弱有关，包括限制细胞因子的产生，包括干扰素-γ和肿瘤坏死因子-α，减少CD107a依赖的脱颗粒，以及抑制DNK的增殖。最后，我们报道了与正常妊娠相比，反复妊娠丢失(RPL)患者蜕膜中几种糖酵解相关酶的蛋白水平改变和mTORC1活性显著降低，这可能为RPL的发病机制提供新的见解。总而言之，我们的数据表明，葡萄糖代谢和mTORC1信号支持DNK在怀孕早期的功能。
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.