Overexpression of lipocalin 2 in PBX1-deficient decidual NK cells promotes inflammation at the maternal-fetal interface
Overexpression of lipocalin 2 in PBX1-deficient decidual NK cells promotes inflammation at the maternal-fetal interface
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DOI：
10.1111/aji.13676
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发表时间：
2023-01-15
影响因子：
3.6
通讯作者：
Wei, Haiming
中科院分区：
文献类型：
--
作者：
An, Xue;Qin, Jingkun;Wei, Haiming
蜕膜自然杀伤（dNK）细胞中PBX 1表达的受损与原因不明的复发性流产的发病机制有关，其通过影响下游生长因子的分泌而导致胎儿生长受限（FGR）。然而，是否有其他机制限制胚胎在含有PBX 1缺陷型自然杀伤（NK）细胞的蜕膜中生长尚不清楚。研究方法：采用Pbx 1（f/f）; Ncr 1（Cre）小鼠，探讨PBX 1（-）NK细胞影响胚胎发育的机制。为了模拟孕妇的临床测试，使用多普勒超声成像来检测胚胎植入和发育。采用RNA测序和实时荧光定量PCR技术筛选PBX 1（-）NK细胞中可能影响正常妊娠的差异表达基因（DEG）。用流式细胞仪检测DEG对免疫细胞的影响。最后，通过将与所选择的DEG相对应的蛋白质LCN 2注射到小鼠体内来探索FGR的机制。结果超声多普勒证实Pbx 1（f/f）; Ncr 1（Cre）小鼠胚胎发育异常，并发现dNK细胞LCN 2表达上调。我们还观察到Pbx 1（f/f）; Ncr 1（Cre）小鼠蜕膜中嗜中性粒细胞和巨噬细胞浸润较高。最后，我们发现在将LCN 2注射到妊娠小鼠中后，母胎界面处的中性粒细胞的数量和活化增加，并观察到这些小鼠显示出FGR的迹象。结论PBX 1（-）dNK细胞在母胎界面分泌过量的LCN 2，募集中性粒细胞，引起炎症反应，与FGR有关。
ProblemImpairment 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 studyPbx1(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. ResultsWe 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. ConclusionExcessive LCN2 secreted by PBX1(-) dNK cells at the maternal-fetal interface recruit neutrophils and causes an inflammatory response, which is related to FGR.