The IL-33/ILC2 axis in parturition

分娩时的 IL-33/ILC2 轴

• 批准号: 10318956
• 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
• 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/10318956
• 关键词: Address; Adult; Alleles; Archives; Attention; B-Lymphocytes; Biology; Birth; Cell Nucleus; Cells; Data; Decidua; 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 of activation protein; 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; Time; Tissues; Uterine Contraction; Uterus; cell type; cytokine; experimental study; insight; myometrium; neonatal morbidity; novel; pregnant; receptor; response; senescence; unpublished works; uterine contractility

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，因为它发生时没有血清的下降。 孕酮(P4)水平。然而，这一过程仍然是个谜：不仅孕长乘以时钟的性质完全不清楚，而且人们对足月妊娠时启动的最终导致子宫收缩的细胞和分子事件的序列也知之甚少。不幸的是，子宫固有的分娩途径还没有被机械地解剖，因为在小鼠和大鼠身上进行的研究转而解决了这些物种叠加的内分泌介导的分娩途径，涉及卵巢停止P4合成(即黄体溶解)。这在知识上留下了一个根本性的鸿沟，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治疗方法的努力，早产是新生儿发病率和死亡率的主要原因。在这里，我们讨论了IL-1细胞因子家族成员IL-33及其关键靶细胞类型--第2组固有淋巴样细胞(ILC2)是如何控制分娩的。引人注目的是，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P4以避开黄体溶解的影响时无法启动分娩。相比之下，P4处理的Rag2-/-小鼠缺乏T和B细胞，但保留了固有的淋巴细胞，进行分娩的时间与B6对照组相当。我们还发现，随着妊娠的提前，ILC2s以一种依赖于IL-33的方式在子宫肌层中扩张，而IL-33主要由其间质成分在妊娠晚期子宫内产生。综上所述，这些结果表明，ILC2在子宫肌层内的激活，在妊娠晚期由子宫基质细胞产生的IL-33启动，是小鼠子宫固有分娩途径的关键组成部分。我们建议以了解IL-33/ILC2轴如何参与正常人类分娩和早产的病理生理学来证实这一假说。该提案有三个具体目标。目标1将使用在IL-33/ST2轴上具有不同子宫和细胞类型特定缺陷的小鼠来描述分娩期间对IL-33和ILC2s的确切细胞和时间需求。然后，目标2将确定IL-33促进分娩的效应机制，首先评估我们初步数据所建议的已知分娩成分和潜在的候选途径，然后采取公正的方法揭示更多的下游候选途径。目的3将评估IL-33/ILC2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。总而言之，我们希望这些研究为推动小鼠分娩的关键的子宫内在调节电路提供明确的细胞和分子定义。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障碍中是如何失调的开辟了新的途径。