The IL-33/ILC2 axis in parturition

人类的分娩被认为是子宫内的过程，因为它发生时血清水平没有下降 孕酮（P4）水平。然而，这一过程仍然是神秘的：不仅是“时钟”的性质，时间妊娠长度完全模糊，但鲜为人知的是，在足月妊娠，最终达到高潮的细胞和分子事件的顺序。不幸的是，子宫内在分娩途径还没有被机械地解剖，因为在小鼠和大鼠中进行的研究已经解决了这些物种的叠加的内分泌介导的分娩途径，其涉及卵巢P4合成的关闭（即黄体溶解）。这就留下了一个根本性的知识空白，对人类健康产生了深远的负面影响，因为它排除了为早产开发合理疗法的尝试，而早产是新生儿发病率和死亡率的主要原因。在这里，我们解决分娩是如何控制的IL-1细胞因子家族成员IL-33及其关键的靶细胞类型，组2先天淋巴样细胞（ILC 2）。引人注目的是，我们已经发现，IL-33缺陷型小鼠以及缺乏所有淋巴细胞（包括ILC 2）的Rag 2-/-Il 2 rg-/-小鼠在补充外源性P4以规避黄体溶解的影响时不能启动分娩。相比之下，P4处理的Rag 2-/-小鼠缺乏T和B细胞，但保留先天淋巴样细胞经历分娩与B6对照相当的时间。我们还发现ILC 2在子宫肌层中以IL-33依赖的方式随着妊娠的进展而扩增，并且IL-33主要由其基质成分在妊娠晚期子宫内产生。总之，这些结果表明，子宫肌层内的ILC 2激活，在妊娠晚期由子宫基质细胞产生的IL-33启动，是小鼠分娩子宫内在途径的关键组成部分。我们建议证实这一假设的最终目标是了解IL-33/ILC 2轴可能参与正常人类分娩和早产的病理生理学。该提案有三个具体目标。目的1将使用在IL-33/ST 2轴中具有各种子宫和细胞类型特异性缺陷的小鼠来描绘分娩中对IL-33和ILC 2的确切细胞和时间需求。目标2将通过首先评估已知的分娩组分和我们的初步数据所建议的潜在候选途径，然后通过采取无偏倚的方法来揭示其他下游候选途径，来确定IL-33促进分娩的效应机制。目的3将评估IL-33/ILC 2轴是否参与小鼠早产的病理生理学，并通过分析存档的子宫切除标本，评估人类足月和早产的病理生理学。总之，我们期望这些研究为驱动小鼠分娩的关键子宫内在调节回路提供明确的细胞和分子定义。因此，它们可能为解剖人类分娩机制以及确定这些机制在人类妊娠障碍中如何失调开辟新的途径。

Parturition in humans is thought to be a uterus-intrinsic process since it occurs without a decline in the serum progesterone (P4) levels. However, this process remains mysterious: not only is the nature of the “clock” that times gestation length completely obscure, but little is known about the sequence of cellular and molecular events initiated at term gestation that ultimately culminate in uterine contraction. Unfortunately, uterus-intrinsic parturition pathways have not been dissected mechanistically, as studies performed in mice and rats have instead addressed these species' superimposed, endocrine-mediated parturition pathway that involves shutdown of P4 synthesis by the ovary (i.e. luteolysis). This leaves a fundamental gap in knowledge with profound negative implications for human health since it precludes attempts to develop rational therapies for preterm birth, a major cause of neonatal morbidity and mortality. Here, we address how parturition is controlled by the IL-1 cytokine family member IL-33 and its key target cell type, the group 2 innate lymphoid cell (ILC2). Strikingly, we have found that IL-33 deficient mice as well as Rag2-/- Il2rg-/- mice lacking all lymphocytes including ILC2s are unable to initiate parturition when they are supplemented with exogenous P4 to circumvent the impact of luteolysis. In contrast, P4-treated Rag2-/- mice lacking T and B cells but retaining innate lymphoid cells undergo parturition with comparable timing to B6 controls. We have also found that ILC2s expand in the myometrium with advancing gestation in an IL-33-dependent fashion, and that IL-33 is produced within the late gestation uterus primarily by its stromal constituents. Together, these results suggest that ILC2 activation within the myometrium, initiated in late gestation by IL-33 produced by uterine stromal cells, is a key component of the uterus-intrinsic pathway of parturition in mice. We propose to substantiate this hypothesis with the ultimate goal of understanding how the IL-33/ILC2 axis might be involved in normal human parturition and the pathophysiology of preterm birth. The proposal has three Specific Aims. Aim 1 will use mice with various uterus- and cell type-specific defects in the IL-33/ST2 axis to delineate the exact cellular and temporal requirements for IL-33 and ILC2s in parturition. Aim 2 will then identify the effector mechanisms through which IL-33 promotes parturition by first evaluating known parturition components and potential candidate pathways suggested by our preliminary data, and then by taking unbiased approaches to reveal additional downstream candidates. Aim 3 will then evaluate whether the IL-33/ILC2 axis is involved in the pathophysiology of preterm parturition in mice and, by analyzing archived hysterectomy specimens, in term and preterm parturition in humans. Together, we expect these studies to provide clear cellular and molecular definition to a key, uterus-intrinsic regulatory circuit that drives parturition in mice. As such, they might open up new avenues for dissecting the mechanisms of human parturition and for determining how such mechanisms are dysregulated in disorders of human pregnancy.