GAS6-mediated dialogue between decidual stromal cells and macrophages is essential for early pregnancy maintenance by inducing M2-like polarization and cell proliferation of decidual macrophages
GAS6-mediated dialogue between decidual stromal cells and macrophages is essential for early pregnancy maintenance by inducing M2-like polarization and cell proliferation of decidual macrophages
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DOI：
10.1093/molehr/gaac006
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发表时间：
2022-03-16
影响因子：
4
通讯作者：
Hu, Li-Na
中科院分区：
文献类型：
--
作者：
Dai, Jing-Cong;Yang, Jia-Yan;Hu, Li-Na
母体对半异基因胎儿的免疫耐受对正常妊娠(NP)至关重要。作为一种分泌蛋白，生长抑制因子6(Gas6)通过诱导肿瘤相关的巨噬细胞转化为免疫抑制的M2样表型来促进癌症的进展。然而，关于Gas6是否调节早期母胎界面蜕膜巨噬细胞(DM Phi S)的研究很少。在这项研究中，早孕蜕膜组织取自选择终止妊娠的正常孕妇和流产患者。检测蜕膜组织中Gas6及其受体(Ax1、Tyro3和MERTK)的表达及蜕膜基质细胞分泌Gas6的情况。然后，我们研究了重组人Gas6(RhGAS6)对从NP和THP-1细胞分离的DM Phi S的影响，并揭示了其机制。流产组DSCs中Gas6和MERTK的表达以及DSCs分泌的Gas6均显著低于正常对照组。此外，我们观察到，重组人GAS6使DM Phi S和THP-1细胞极化为M2样表型，CD163表达上调证明了这一点。此外，重组人GAS6还通过上调CD163的表达，促进DMPhi S清除有毒的游离血红蛋白，并促进DM Phi S和THP-1细胞的增殖。最后，我们证明了rhGAS6通过激活PI3K/Akt信号通路来刺激CD163的表达和细胞增殖。综上所述，这些发现表明DSCs和DM Phi S之间由Gas6介导的对话对于母胎免疫耐受的建立和维持是至关重要的，DSCs分泌Gas6的减少可能导致妊娠早期流产的发生。
Maternal immunotolerance towards the semi-allogeneic foetus is critical for normal pregnancy (NP). As a secretory protein, growth arrest-specific factor 6 (GAS6) promotes cancer progression by inducing the conversion of tumour-associated macrophages to an immunosuppressive M2-like phenotype. However, little is known about whether GAS6 regulates decidual macrophages (dM phi s) in the early maternal-foetal interface. In this study, first-trimester decidual tissues were obtained from normal pregnant women undergoing elective terminations and patients with miscarriages. The expression of GAS6 and its receptors (AXL, TYRO3 and MERTK) in decidua and GAS6 secretion by decidual stromal cells (DSCs) was measured. Then, we investigated the effect of recombinant human GAS6 (rhGAS6) on dM phi s isolated from NP and THP-1 cells, and revealed the underlying mechanism. Both the expression of GAS6 in DSCs and MERTK in dM phi s, in addition to GAS6 secretion by DSCs, was found to be significantly decreased in miscarriage patients compared to that in NPs. Additionally, we observed that rhGAS6 polarized dM phi s and THP-1 cells towards an M2-like phenotype, as evidenced by the up-regulated CD163 expression. Moreover, rhGAS6 enhanced the clearance of toxic cell-free haemoglobin by dM phi s by up-regulating CD163 expression, and rhGAS6 also boosted cell proliferation of dM phi s and THP-1 cells. Finally, we demonstrated that rhGAS6 stimulated CD163 expression and cell proliferation by activating the PI3K/Akt signalling pathway. Collectively, these findings suggest that GAS6-mediated dialogue between DSCs and dM phi s is crucial for the establishment and maintenance of maternal-foetal immunotolerance, and decreased GAS6 secretion by DSCs may lead to the occurrence of miscarriage in the first trimester.