Wenjie Sun’s research while affiliated with Lanzhou University and other places

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Publications (2)

Role of NK cells in normal pregnancy. NK cells are essential in normal pregnancy, balancing immune tolerance and tissue remodelling. Glycodelin inhibits pNK cell cytotoxicity by downregulating perforin, granzyme B and IFN‐γ through KIR receptors, while progesterone induces caspase‐dependent pNK cell apoptosis via PR. Trophoblasts and ESCs recruit pNK cells by expressing chemokines, including MIP‐1α, MIP‐1β, CCRL2, CXCL6, CXCL9, CXCL10, CXCL11 and CXCL12, with LIF limiting excessive NK cell migration to the uterus. Factors secreted by DSCs, such as cAMP, NOS‐2, TGF‐β, IL‐15, GdA and IL‐24, promote dNK cell proliferation and differentiation by activating pathways like STAT3, NFIL3 and Notch1 via NKp46. Trophoblast‐secreted factors, including IL‐2, IL‐15, RAET1, DNAM‐1 and P‐selectin, activate pathways such as ERK, mTORC1, PI3K and AKT through NKp44 and NKG2D, inducing dNK cells to secrete VEGF, IL‐8, IFN‐γ, TNF‐α, and growth factors that support trophoblast proliferation, uterine spiral artery remodelling, and vascular dilation. Additionally, trophoblast‐derived IL‐24, IDO, TGF‐β, IL‐33, HLA‐E and HLA‐G interact with inhibitory receptors like NKG2A and KIR2DL1, suppressing perforin and granzyme B expression, enhancing IL‐10 secretion and maintaining immune tolerance. Activation of KIR2DS1/4 supports GM‐CSF secretion by dNK cells, collectively inhibiting inflammatory cell activity, promoting trophoblast proliferation and invasion, and facilitating uterine vascular remodelling.
Role of NK cells in RSA. In RSA, CD56dim NK cells increase, showing elevated expression of receptors like CD94, CD69, CD161 and NKG2C, alongside decreased inhibitory receptors such as LILRB1 and Tim‐3, leading to increased IFN‐γ secretion and cytotoxicity. TGF‐β in the blood inhibits pNK cells from acquiring CD16, thereby suppressing their differentiation. Eomes‐deficient mice fail to develop NK cells. Other factors, such as IL‐1β‐511T>C and IL‐2, enhance NK cell cytotoxicity and increase susceptibility to RSA. Chemokines like XCL1, CCL5 and CX3CL1 recruit cytotoxic CD56dim CD16high NK cells, and CX3CL1 induces high Ly49 receptor expression in CD49b⁺ dNK cells. DSC autophagy inhibition increases IGF‐2 expression, activating dNK cells via NKG2D and NKp46, enhancing perforin release and inducing trophoblast apoptosis. TNF‐α, IL‐1β and LPS upregulate AhR in dNK cells, while elevated AEA levels induce TNF‐α secretion, exacerbating inflammation. Abnormal activating receptor expression, such as KIR2DS1 interacting with HLA‐C2 ligands, impairs pregnancy outcomes. The decrease in PBX1 expression in dNK cells leads to insufficient activation of AKT1, which results in inadequate expression of pleiotrophin and osteoglycin, thereby contributing to RSA. When HLA‐G expression in trophoblast cells, BMAL1 and UCHL1 expression in decidual cells, and IGF‐1 expression in stromal cells are insufficient, or NRP1 expression in DSCs is reduced, or PIBF levels are elevated, NK cell numbers increase, enhancing their cytotoxic activity. Decreased expression of IFN‐γ, Granzyme B, PRX‐2 and PEDF in NK cells, or elevated granulysin levels, can inhibit the invasive and migratory abilities of trophoblast cells, ultimately leading to RSA.
Role of NK cells in RIF. In RIF, the concentration of CD56dim CD69⁺ NK cells and CD8⁻ NK cells increases. The elevation of these pNK cells promotes the expression of TNF‐α, IFN‐γ, granzyme B and GM‐CSF, or inhibits the expression of membranous Tim‐3, IL‐4 and IL‐10, which can negatively impact ovarian function and reproduction. In patients with RIF, the significant increase in CD56dim dNK cells in the uterus leads to their hyperactivity, reducing endometrial tolerance and ultimately resulting in RIF. The decreased expression of inhibitory receptors on uNK cells, such as KIR2DL1/S1 and LILRB1, along with insufficient expression of HLA‐C, HLA‐G and HLA‐F in trophoblast cells, reduces uNK cell degranulation activity and decreases VEGF and TNF‐α production, contributing to RIF. Additionally, an increased number of CD16⁺ uNK cells and a decreased proportion of CD56bright uNK cells lead to elevated IL‐6 levels. Moreover, decreased IL‐15 and increased IL‐18 expression in trophoblast cells result in insufficient proliferation and activation of uNK cells, while IL‐18, in combination with IL‐2, enhances IFN‐γ production and the cytotoxic activity of uNK cells. Furthermore, the decreased expression of TWEAK in uNK cells and the increased expression of its receptor Fn14 alter uNK cytotoxicity, disrupt decidual homeostasis and ultimately lead to foetal rejection.
Psychosocial and environmental factors associated with pregnancy failure. Psychosocial factors, including workplace competition, high treatment costs, depression and anxiety, reduce NK cell numbers and inhibit their proliferation and activity. Environmental factors, such as air pollution, alcohol consumption and exposure to synthetic chemicals, suppress IL‐17 signalling in NK cells, decreasing α‐SMA and VEGF levels. Abnormal m6A methylation accumulation at the IGF2BP1 promoter induces endometrial atrophy, enhances NK cell cytotoxicity and contributes to pregnancy failure.
Role of microorganisms in pregnancy failure. Toxoplasma gondii infection stimulates decidual dendritic cells (dDCs) to secrete IL‐12, which enhances NKG2D expression in dNK cells and activates the NF‐κB signalling pathway. This results in increased secretion of IFN‐γ, TNF‐α and granzyme B, heightening dNK cell cytotoxicity. TGF‐β signalling is suppressed during infection, weakening maternal‐foetal immune tolerance. T. gondii infection reduces Tim‐3 expression while promoting NKG2D expression in dNK cells, activating the PI3K‐AKT and JAK‐STAT pathways. These changes upregulate granzyme B, granzyme A, perforin, IFN‐γ and IL‐10 production, contributing to adverse pregnancy outcomes. Additionally, T. gondii activates the JNK/FOXO1 pathway, reducing Gal‐9 expression in decidual macrophages. The loss of Gal‐9 disrupts the Gal‐9/Tim‐3 interaction, impairing dNK cell function by inducing ERK phosphorylation, inhibiting p‐CREB and IL‐10 expression and promoting T‐bet and IFN‐γ expression, further exacerbating adverse outcomes. The infection downregulates 2B4 expression, increasing TNF‐α and IFN‐γ secretion. Furthermore, T. gondii elevates HLA‐G levels in trophoblast cells, increases caspase‐3 and caspase‐8 activity in dNK cells, and induces apoptosis. Porphyromonas gingivalis suppresses IL‐18 production by dNK cells, impairing spiral artery remodelling and reducing EVT invasion. Lipopolysaccharide (LPS) activates TLR3 in dNK cells, upregulating CD69, TNF‐α and IFN‐γ expression. Human cytomegalovirus (HCMV) enhances NK cell cytotoxicity via NKG2D and NKG2C, while HHV‐6 increases chemokine receptor expression (CCR2, CXCR3 and CX3CR1) through the NKG2D‐FasL pathway. Zika virus (ZIKV) induces endoplasmic reticulum (ER) stress, downregulating inhibitory receptor ligands HLA‐C and HLA‐G on trophoblast cells, rendering them targets for dNK cells. ER stress activates NKp46, leading to high levels of IFN‐γ and TNF‐α production by dNK cells, which ultimately kill ZIKV‐infected trophoblasts.

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Dual Role of Natural Killer Cells in Early Pregnancy: Immunopathological Implications and Therapeutic Potential in Recurrent Spontaneous Abortion and Recurrent Implantation Failure
  • Literature Review
  • Full-text available

May 2025

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46 Reads

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1 Citation

Defeng Guan

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Zhou Chen

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Yuhua Zhang

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Xia Huang

Natural killer (NK) cells are critical regulators of immune processes during early pregnancy, playing a key role in maintaining maternal‐foetal immune tolerance and supporting successful implantation. In particular, uterine NK cells, a specialised subset of NK cells, facilitate trophoblast invasion, spiral artery remodelling and placental establishment. Dysregulation of NK cell activity, however, has been implicated in pregnancy complications, notably recurrent spontaneous abortion (RSA) and recurrent implantation failure (RIF). Aberrant NK cell functions, such as heightened cytotoxicity or defective immune signalling, can disrupt the balance between immune tolerance and response, leading to impaired placental development, reduced trophoblast activity and compromised uteroplacental blood flow. This review examines the role of NK cells in early pregnancy, emphasising their contributions to immune modulation and placentation. It also investigates the mechanisms by which NK cell dysfunction contributes to RSA and RIF, and explores therapeutic strategies aimed at restoring NK cell balance to improve pregnancy outcomes. A deeper understanding of NK cell interactions during early pregnancy may provide critical insights into the pathogenesis of pregnancy failure and facilitate targeted immunotherapeutic approaches.

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Citations (1)

... Despite advances in understanding the pathogenesis of immune-related RSA, current therapeutic strategies remain limited, mainly focusing on immunosuppressive treatments or interventions to enhance maternal-fetal tolerance. [9] However, these methods are frequently associated with side effects and do not consistently address the underlying immune dysregulation in all cases. [10] As a result, there is growing interest in traditional Chinese medicine (TCM) as a complementary and alternative treatment, particularly in the management of immune-related conditions like RSA, where TCM has demonstrated some efficacy. ...

Reference:

Traditional Chinese medicine syndrome patterns in immune-related recurrent spontaneous abortion: A cross-sectional observational study based on cluster analysis
Immunologic insights in recurrent spontaneous abortion: Molecular mechanisms and therapeutic interventions
  • Citing Article

  • July 2024

Biomedicine & Pharmacotherapy

Defeng Guan

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Wenjie Sun

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Mingxia Gao

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Xiaoling Ma