The IL-33/ILC2 axis in parturition

分娩时的 IL-33/ILC2 轴

基本信息

批准号：
10543446
负责人：
Adrian Erlebacher
金额：
$ 64.06万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543446
关键词：
Address Adult Alleles Archives Attention B-Lymphocytes Biology Birth Cell Nucleus Cells Data Decidua Dedications Defect Disease Endocrine Event Family member Fetus Functional disorder Goals Health Human Hysterectomy Immune response Immunofluorescence Immunologic Immunologics Incidence Induced Labor Inflammation Inflammatory Injections Interleukin-1 Knowledge Labor Onset Length Link Luteolysis Lymphocyte Lymphoid Cell Measures Mechanics Mediating Mediator Modeling Molecular Mus Nature Neonatal Mortality Ovary Pathway interactions Placenta Pregnancy Premature Birth Process Progesterone Rattus Serum Signal Transduction Smooth Muscle Specimen Stretching Stromal Cells T-Lymphocyte TP53 gene Testing Tissues Uterine Contraction Uterus cell type cytokine experimental study insight myometrium neonatal morbidity novel pregnant receptor response senescence unpublished works uterine contractility

项目摘要

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.

人类的分娩被认为是子宫固有的过程，因为它发生时血清不会下降然而，这个过程仍然很神秘：不仅计时妊娠长度的“时钟”的本质完全模糊，而且人们对足月妊娠时启动并最终达到高潮的细胞和分子事件的顺序知之甚少。不幸的是，子宫固有的分娩途径尚未被机械地剖析，因为在小鼠和大鼠中进行的研究却解决了这些物种的叠加的、内分泌介导的分娩途径。这涉及到卵巢 P4 合成的关闭（即黄体溶解），这在知识上留下了根本性的空白，对人类健康产生了深远的负面影响，因为它阻碍了针对早产（新生儿发病和死亡的主要原因）开发合理疗法的尝试。在这篇文章中，我们探讨了 IL-1 细胞因子家族成员 IL-33 及其关键靶细胞类型（第 2 组先天淋巴细胞 (ILC2)）如何控制分娩。令人惊讶的是，我们发现： IL-33 缺陷小鼠以及缺乏包括 ILC2 在内的所有淋巴细胞的 Rag2-/- Il2rg-/- 小鼠在补充外源性 P4 以避免黄体溶解的影响时无法开始分娩。相反，P4 处理的 Rag2-/ 小鼠无法开始分娩。 - 缺乏 T 和 B 细胞但保留先天淋巴细胞的小鼠的分娩时间与 B6 对照组相当。我们还发现 ILC2 在子宫肌层中随着前进而扩张。妊娠以 IL-33 依赖性方式进行，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，ILC2 在子宫肌层内的激活是在妊娠晚期由 IL-33 产生的。子宫基质细胞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，最终目标是了解分娩过程是如何发生的。 IL-33/ILC2 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：目标 1 将使用 IL-33/ST2 轴具有各种子宫和细胞类型特异性缺陷的小鼠。目标 2 将通过首先评估已知的情况来确定 IL-33 促进分娩的效应机制。 Aim 3 将评估 IL-33/ILC2 轴是否参与小鼠早产的病理生理学。通过分析人类足月和早产的存档子宫切除标本，我们期望这些研究能够为驱动子宫内在的关键调节回路提供清晰的细胞和分子定义。因此，它们可能为剖析人类分娩机制以及确定这些机制在人类妊娠疾病中如何失调开辟新途径。