The IL-33/ILC2 axis in parturition

分娩时的 IL-33/ILC2 轴

• 批准号: 10083186
• 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/10083186
• 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cytokine; experimental study; insight; myometrium; neonatal morbidity; novel; pregnant; receptor; response; senescence; unpublished works; uterine contractility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内在过程，因为串行没有下降 孕酮（P4）水平。然而，这个过程仍然是神秘的：妊娠长度完全晦涩难懂的“时钟”的性质不仅是对在术语妊娠中发起的细胞和分子事件的序列，最终最终导致子宫收缩中的序列。不幸的是，由于在小鼠和大鼠中进行的研究已经解决了这些物种叠加的，内分泌介导的分娩途径，因此涉及卵巢中P4合成（即小脂溶液）。这留下了知识的根本差距，对人类健康产生了深远的负面影响，因为它排除了试图开发早产的理性疗法，这是新生儿发病率和死亡率的主要原因。在这里，我们解决了如何由IL-1细胞因子家族成员IL-33及其关键靶细胞类型（第2组先天淋巴样细胞（ILC2））控制的分娩。令人惊讶的是，我们发现IL-33缺陷小鼠以及RAG2 - / - IL2RG - / - 小鼠缺乏包括ILC2在内的所有淋巴细胞时无法启动分娩，以避免外源性P4来避免luteolsosiss的影响。相比之下，缺乏T和B细胞的P4处理的RAG2 - / - 小鼠，但保留了先天淋巴样细胞的分娩，并且与B6对照相当。我们还发现，ILC2在肌层中以IL-33依赖性方式前进的妊娠在肌层中扩展，并且IL-33是在晚期妊娠子宫内部产生的，其基质构成。总之，这些结果表明，子宫基质细胞产生的IL-33在晚期妊娠中的肌层中的ILC2激活是小鼠分娩的子宫内术途径的关键成分。我们建议证实这一假设，其最终目的是了解IL-33/ILC2轴如何参与正常的人类分娩和早产的病理生理学。该提案具有三个具体目标。 AIM 1将使用IL-33/ST2轴中具有各种子宫和细胞类型特异性缺陷的小鼠来划定IL-33和ILC2的精确细胞和临时要求。然后，AIM 2将确定IL-33通过首先评估已知的分娩组件以及我们的初步数据建议的潜在候选途径，然后采用无偏见的方法来揭示额外的下游候选者，从而确定IL-33促进分娩的效应机制。然后，AIM 3将评估IL-33/ILC2轴是否参与小鼠早产的病理生理学，并通过分析的存档子宫切除术在人类的术语和早产。我们期望这些研究共同为驱动小鼠分娩的钥匙，子宫内膜调节回路提供明显的细胞和分子定义。因此，他们可能会开辟新的途径来剖析人类分娩的机制，并确定这种机制在人类妊娠疾病中如何失调。