Pro- and Anti-Inflammatory Cytokines in the Context of NK Cell–Trophoblast Interactions

Михайлова, В. А.; Grebenkina, Polina; Khokhlova, Evgeniia; Davydova, A. A.; Salloum, Zeina; Tyshchuk, Elizaveta; Zagainova, Valeria; Маркова, К. Л.; Kogan, Igor Yu.; Selkov, S. A.; Sokolov, D. N.

doi:10.3390/ijms23042387

Cited by 12 publications

(7 citation statements)

References 58 publications

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“…Both trophoblasts and natural killers have a wide arsenal for mutual containment, since trophoblasts are considered foreign elements by the mother’s immune system. On the other hand, the invasion of trophoblasts into the endometrium is accompanied by their influence on cells of the microenvironment, including endometrial, endothelial, and maternal NK cells [ 94 , 95 , 96 , 97 ]. Despite this, NK cells actively control the proliferation and migration of trophoblasts under conditions of physiological pregnancy, which in turn restrains the excessive cytotoxicity of NK cells [ 98 , 99 , 100 , 101 ].…”

Section: Discussionmentioning

confidence: 99%

Natural Killer Cell Derived Microvesicles Affect the Function of Trophoblast Cells

et al. 2023

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The interaction of natural killer (NK) and trophoblast cells underlies the formation of immune tolerance in the mother–fetus system and the maintenance of the physiological course of pregnancy. In addition, NK cells affect the function of trophoblast cells, interacting with them via the receptor apparatus and through the production of cytokines. Microvesicles (MVs) derived from NK cells are able to change the function of target cells. However, in the overall pattern of interactions between NK cells and trophoblasts, the possibility that both can transmit signals to each other via MVs has not been taken into account. Therefore, the aim of this study was to assess the effect of NK cell-derived MVs on the phenotype, proliferation, and migration of trophoblast cells and their expression of intracellular messengers. We carried out assays for the detection of content transferred from MV to trophoblasts. We found that NK cell-derived MVs did not affect the expression of CD54, CD105, CD126, CD130, CD181, CD119, and CD120a receptors in trophoblast cells or lead to the appearance of CD45 and CD56 receptors in the trophoblast membrane. Further, the MVs reduced the proliferation but increased the migration of trophoblasts with no changes to their viability. Incubation of trophoblast cells in the presence of MVs resulted in the activation of STAT3 via pSTAT3(Ser727) but not via pSTAT3(Tyr705). The treatment of trophoblasts with MVs did not result in the phosphorylation of STAT1 and ERK1/2. The obtained data indicate that NK cell-derived MVs influence the function of trophoblast cells, which is accompanied by the activation of STAT3 signaling.

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Section: Discussionmentioning

confidence: 99%

Natural Killer Cell Derived Microvesicles Affect the Function of Trophoblast Cells

et al. 2023

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“…There are a considerable number of dNK cells in the decidua, accounting for approximately 70% of the total number of deciduous lymphocytes [ 27 ]. During pregnancy, the decidua maintains close contact with trophoblasts without causing damage because trophoblasts exert an immunosuppressive effect on dNK cells [ 28 ]. NK cells in the decidua are a dominant subpopulation, and various factors with inhibitory effects on NK cells are locally present.…”

Section: Discussionmentioning

confidence: 99%

Palmitic Acid Upregulates CD96 Expression to Mediate Maternal–Foetal Interface Immune Tolerance by Inhibiting Cytotoxic Activity and Promoting Adhesion Function in Human Decidual Natural Killer Cells

Wang,

Wang

2023

Bioengineering

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Decidual natural killer cells (dNK cells) are an essential component of the immune cells present at the maternal–foetal interface during early pregnancy, and they play a vital role in various physiological processes. Abnormalities in the ratio or function of dNK cells have been linked to recurrent miscarriages. CD96 has been previously shown to regulate NK cell function in the tumour microenvironment; however, its role and mechanism at the maternal–foetal interface remains unclear. The present study aimed to investigate the immunomodulatory role of CD96 in dNK cells and its function at the maternal–foetal interface. Immunofluorescence staining and flow cytometry were used to detect the expression of cellular markers such as CD96. Furthermore, the secretory function, adhesion-function-related molecules, and cell proliferation markers of CD96+ and CD96− dNK cells were detected using flow cytometry. In addition, we performed cell culture experiments via the magnetic bead sorting of NK cells to detect changes in the expression of the aforementioned functional molecules in dNK cells after the CD96 blockade. Furthermore, we examined the functional characteristics of dNK cells after palmitic acid treatment at a concentration of 10 μM. We also examined the changes in dNK cell function when subjected to the combined effect of palmitic acid and CD96 antagonists. The results indicated that CD96, TIGIT, CD155, and CD112 were highly expressed at the maternal–foetal interface, with dNK cells predominantly expressing CD96, whereas TIGIT was mainly expressed on T cells, and CD155 and CD112 were mainly present in metaphase stromal and trophoblast cells. CD96+ dNK cells displayed low cytotoxic activity and a high adhesion phenotype, which mediated the immunosuppressive effect on dNK cells at the maternal–foetal interface. Palmitic acid upregulated CD96 expression on the surface of dNK cells in the coculture system, inhibiting dNK cell activity and increasing their adhesion molecule expression. CD96 antagonist treatment blocked the inhibitory effect of trophoblasts on dNK cells, resulting in enhanced cytokine secretion and reduced adhesion. The results of this study provide valuable insight into the immunomodulatory role of CD96 in dNK cells and its mechanism at the maternal–foetal interface, particularly in metaphase NK cells. This study sheds light on the mechanisms of immune regulation at the maternal–foetal interface and their implications for the study of recurrent miscarriages of unknown origin.

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“…However, under certain circumstances, dNK cells might become embryotoxic, 3 as illustrated by the fact that embryo resorption is associated with elevated levels of tumor necrosis factor (TNF)‐α and interleukin (IL)‐6 expression in utero, which can be prevented by NK cell depletion 13–15 . Recent reports have also mentioned that inflammatory or anti‐inflammatory factors in the microenvironment of the maternal‐fetal interface can also affect the phenotypic characteristics of NK cells and change their functional activity, thereby affecting the interaction between dNK cells and trophoblast cells 16 . Abnormal interactions between trophoblasts and dNK cells underlie common disorders of pregnancy, including preeclampsia, fetal growth restriction (FGR), and recurrent miscarriage 6,17,18 .…”

Section: Introductionmentioning

confidence: 99%

“…[13][14][15] Recent reports have also mentioned that inflammatory or anti-inflammatory factors in the microenvironment of the maternal-fetal interface can also affect the phenotypic characteristics of NK cells and change their functional activity, thereby affecting the interaction between dNK cells and trophoblast cells. 16 Abnormal interactions between trophoblasts and dNK cells underlie common disorders of pregnancy, including preeclampsia, fetal growth restriction (FGR), and recurrent miscarriage. 6,17,18 These findings all suggest a potential role for inflammatory dNK cells in pregnancy failure.…”

mentioning

confidence: 99%

Overexpression of lipocalin 2 in PBX1‐deficient decidual NK cells promotes inflammation at the maternal‐fetal interface

Xue

Qin

et al. 2023

American J Rep Immunol

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Problem: Impairment of PBX1 expression in decidual natural killer (dNK) cells is associated with the pathogenesis of unexplained recurrent spontaneous abortion, which results in fetal growth restriction (FGR) by affecting the secretion of downstream growth factors. However, whether other mechanisms limit embryo growth in decidua containing PBX1-deficient natural killer (NK) cells is unknown.Method of study: Pbx1 f/f ; Ncr1 Cre mice were employed to explore the underlying mechanisms by which PBX1 − NK cells affect embryonic development. To simulate the clinical testing of pregnant women, Doppler ultrasound imaging was used to detect embryo implantation and development. Differentially expressed genes (DEGs) in PBX1 − NK cells that may affect normal pregnancy were screened using RNA-sequencing and real-time PCR. Immune cell changes caused by DEGs were detected by flow cytometry. Finally, the mechanism of FGR was explored by injecting the protein LCN2, corresponding to the selected DEG, into mice. Results:We verified the embryonic dysplasia in pregnant Pbx1 f/f ; Ncr1 Cre mice by Doppler ultrasound imaging and found that LCN2 was upregulated in dNK cells. We also observed higher infiltration of neutrophils and macrophages in the decidua of Pbx1 f/f ; Ncr1 Cre mice. Finally, we found an increase in the number and activation of neutrophils at the maternal-fetal interface after injecting LCN2 into pregnant mice and observed that these mice showed signs of FGR. Conclusion:Excessive LCN2 secreted by PBX1 − dNK cells at the maternal-fetal interface recruit neutrophils and causes an inflammatory response, which is related to FGR.

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Pro- and Anti-Inflammatory Cytokines in the Context of NK Cell–Trophoblast Interactions

Cited by 12 publications

References 58 publications

Natural Killer Cell Derived Microvesicles Affect the Function of Trophoblast Cells

Natural Killer Cell Derived Microvesicles Affect the Function of Trophoblast Cells

Palmitic Acid Upregulates CD96 Expression to Mediate Maternal–Foetal Interface Immune Tolerance by Inhibiting Cytotoxic Activity and Promoting Adhesion Function in Human Decidual Natural Killer Cells

Overexpression of lipocalin 2 in PBX1‐deficient decidual NK cells promotes inflammation at the maternal‐fetal interface

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