Unit for Autoimmunity and Immune Regulation, Division of Clinical Immunology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, 581 85 Linköping, Sweden.
J Immunol. 2011 Oct 1;187(7):3671-82. doi: 10.4049/jimmunol.1100130. Epub 2011 Sep 2.
During pregnancy, the maternal immune system is challenged by the presence of the fetus, which must be tolerated despite being semiallogeneic. Uterine mucosal (or decidual) macrophages (M), one of the major leukocyte populations at the fetal-maternal interface, have been implicated in fetal tolerance, but information regarding their regulation is scarce. In this study, we investigated the role of several factors potentially involved in the differentiation and polarization of decidual M with an in vitro M differentiation model. By using flow cytometry, we showed that M-CSF and IL-10 were potent inducers of M2 (immunoregulatory) M markers expressed on human decidual M (CD14, CD163, CD206, CD209). In contrast, proinflammatory stimuli, and unexpectedly also the Th2-associated IL-4 and IL-13, induced different patterns of expression, indicating that a Th2-dominated environment is not required for decidual M polarization. M-CSF/IL-10-stimulated and decidual M also showed similar cytokine secretion patterns, with production of IL-10 as well as IL-6, TNF, and CCL4. Conversely, the proinflammatory, LPS/IFN-γ-stimulated M produced significantly higher levels of TNF and no IL-10. We also used a gene array with 420 M-related genes, of which 100 were previously reported to be regulated in a global gene expression profiling of decidual M, confirming that M-CSF/IL-10-induced M are closely related to decidual M. Taken together, our results consistently point to a central role for M-CSF and in particular IL-10 in the shaping of decidual M with regulatory properties. These cytokines may therefore play an important role in supporting the homeostatic and tolerant immune milieu required for a successful pregnancy.
在妊娠期间，母体免疫系统受到胎儿的挑战，尽管胎儿是半同种异体的，但仍必须耐受。子宫黏膜（或蜕膜）巨噬细胞（M）是胎儿-母体界面主要白细胞群之一，与胎儿耐受有关，但关于其调节的信息很少。在这项研究中，我们通过体外 M 分化模型研究了几种潜在因素在蜕膜 M 分化和极化中的作用。通过流式细胞术，我们显示 M-CSF 和 IL-10 是诱导人蜕膜 M（CD14、CD163、CD206、CD209）上表达的 M2（免疫调节）M 标志物的有效诱导剂。相比之下，促炎刺激物，甚至出人意料的 Th2 相关的 IL-4 和 IL-13，诱导了不同的表达模式，表明 Th2 占主导的环境对于蜕膜 M 的极化不是必需的。M-CSF/IL-10 刺激和蜕膜 M 也表现出相似的细胞因子分泌模式，产生 IL-10 以及 IL-6、TNF 和 CCL4。相反，促炎刺激物，LPS/IFN-γ 刺激的 M 产生了显著更高水平的 TNF 而没有 IL-10。我们还使用了包含 420 个与 M 相关基因的基因芯片，其中 100 个先前在蜕膜 M 的全基因表达谱中被报道受到调节，证实了 M-CSF/IL-10 诱导的 M 与蜕膜 M 密切相关。总之，我们的结果一致表明 M-CSF 特别是 IL-10 在塑造具有调节特性的蜕膜 M 中起着核心作用。这些细胞因子因此可能在支持成功妊娠所需的稳态和耐受免疫环境中发挥重要作用。
