Maternal IL-33 critically regulates tissue remodeling and type 2 immune responses in the uterus during early pregnancy in mice.
Maternal IL-33 critically regulates tissue remodeling and type 2 immune responses in the uterus during early pregnancy in mice.
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DOI：
10.1073/pnas.2123267119
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发表时间：
2022-08-30
影响因子：
11.1
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中科院分区：
文献类型：
--
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最近的临床研究表明，白介素33(IL-33)信号的异常与妇女不良妊娠结局有关，包括反复妊娠丢失、先兆子痫和早产。然而，IL-33如何支持哺乳动物的妊娠进展还不是很清楚。在这里，我们表明，缺乏Il33基因的怀孕小鼠表现出广泛的细胞、生理和免疫缺陷，这些缺陷在怀孕早期就表现出来。我们的数据表明，在妊娠早期，IL-33信号在母胎界面支持不同的促妊娠过程，这反过来又为妊娠后期的最佳结局奠定了基础。最终，我们的发现有可能为针对IL-33的治疗应用和干预提供信息，以改善女性的妊娠结局。怀孕的子宫是一个免疫丰富的器官，在妊娠的关键阶段，炎症环境和免疫细胞功能会发生动态变化。最近的研究表明，白介素1(IL-1)家族细胞因子IL-33及其受体ST2的异常表达与妇女不良妊娠结局有关，包括反复妊娠丢失、先兆子痫和早产。IL-33如何在体内支持怀孕进展尚不清楚。在这里，我们证明了母体IL-33信号在小鼠早期怀孕期间对子宫组织重塑和免疫细胞功能的关键调节。IL-33缺乏的DAM在妊娠早期表现出植入腔形成和蜕膜化的缺陷，以及异常的血管重塑。这些缺陷与早期胚胎发育延迟、吸收增加以及妊娠晚期胎儿和胎盘发育受损不谋而合。在细胞水平上，子宫肌层成纤维细胞、蜕膜内皮细胞和基质细胞是蜕膜形成和早期胎盘形成过程中子宫中主要的IL-33+细胞类型，而ST2由与2型免疫反应相关的子宫免疫群体表达，包括ILC2、Tregs、CD4+T细胞、M2和CDC2样髓样细胞和肥大细胞。IL-33缺乏的DAMM的早期妊娠缺陷与子宫淋巴细胞对2型细胞因子的反应受损以及子宫微环境中精氨酸酶-1+巨噬细胞的减少有关。总而言之，我们的数据突出了一个调控网络，涉及母胎界面上产生IL-33的非免疫细胞和ST2+免疫细胞之间的串扰，这对小鼠的妊娠进展至关重要。这项工作有可能促进我们对IL-33信号如何支持女性最佳妊娠结局的理解。
Recent clinical studies suggest that abnormal interleukin-33 (IL-33) signaling is associated with poor pregnancy outcomes in women, including recurrent pregnancy loss, preeclampsia, and preterm labor. Nevertheless, how IL-33 supports pregnancy progression in mammals is not well understood. Here, we show that pregnant mice lacking the Il33 gene exhibit a broad spectrum of cellular, physiological, and immunological defects that manifest very early in pregnancy. Our data suggest that IL-33 signaling supports diverse, pro-pregnancy processes at the maternal–fetal interface during early gestation, which in turn lay the foundation for optimal outcomes at later stages of pregnancy. Ultimately, our findings have the potential to inform therapeutic applications and interventions that target IL-33 to improve pregnancy outcomes in women. The pregnant uterus is an immunologically rich organ, with dynamic changes in the inflammatory milieu and immune cell function underlying key stages of pregnancy. Recent studies have implicated dysregulated expression of the interleukin-1 (IL-1) family cytokine, IL-33, and its receptor, ST2, in poor pregnancy outcomes in women, including recurrent pregnancy loss, preeclampsia, and preterm labor. How IL-33 supports pregnancy progression in vivo is not well understood. Here, we demonstrate that maternal IL-33 signaling critically regulates uterine tissue remodeling and immune cell function during early pregnancy in mice. IL-33–deficient dams exhibit defects in implantation chamber formation and decidualization, and abnormal vascular remodeling during early pregnancy. These defects coincide with delays in early embryogenesis, increased resorptions, and impaired fetal and placental growth by late pregnancy. At a cellular level, myometrial fibroblasts, and decidual endothelial and stromal cells, are the main IL-33+ cell types in the uterus during decidualization and early placentation, whereas ST2 is expressed by uterine immune populations associated with type 2 immune responses, including ILC2s, Tregs, CD4+ T cells, M2- and cDC2-like myeloid cells, and mast cells. Early pregnancy defects in IL-33–deficient dams are associated with impaired type 2 cytokine responses by uterine lymphocytes and fewer Arginase-1+ macrophages in the uterine microenvironment. Collectively, our data highlight a regulatory network, involving crosstalk between IL-33–producing nonimmune cells and ST2+ immune cells at the maternal–fetal interface, that critically supports pregnancy progression in mice. This work has the potential to advance our understanding of how IL-33 signaling may support optimal pregnancy outcomes in women.
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