The regulatory role of natural progesterone in barrier immunity

天然黄体酮在屏障免疫中的调节作用

• 批准号: 10708998
• 负责人: Florian Hladik
• 金额: $ 86.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708998
• 关键词: Address; Affect; Antibodies; Antigen-Presenting Cells; Antiinflammatory Effect; Asthma; Autoimmune Diseases; Bar Codes; Biopsy; Blood; Bone Marrow; CCL2 gene; CCL4 gene; Cell Count; Cells; Chimera organism; Chlamydia trachomatis; Clinic Visits; Clinical; Color; Data; Dendritic Cells; Disease; Estradiol; Estrogen Therapy; Estrogens; Exhibits; Female; Flow Cytometry; Frequencies; Gastrointestinal tract structure; Genes; Gonadal Steroid Hormones; HIV; Hormones; Human; Immune; Immune system; Immunity; Immunologic Factors; Immunologic Receptors; Immunologics; Immunosuppression; Infection; Inflammatory; Inflammatory Bowel Diseases; Interferons; Interleukins; Knowledge; Leukocytes; Link; Luteal Phase; Luteinizing Hormone; Macrophage; Measures; Mediating; Membrane Proteins; Menstrual cycle; Mucous Membrane; Mus; Natural Immunity; Nose; Oligonucleotides; Phase; Physiological; Population; Postmenopause; Predisposition; Premature Birth; Production; Progesterone; Progesterone Receptors; Property; Receptor Gene; Rectum; Resistance to infection; Rheumatoid Arthritis; Role; Serum; Signal Transduction; Site; Skin; Symptoms; Synthetic Progestogens; Testing; Tissues; Upper respiratory tract; Vaccination; Vagina; Visit; Woman; Women' s Health; adaptive immunity; aged; asthma exacerbation; cervicovaginal; chemokine; cohort; cytokine; experience; experimental study; falls; immune function; improved; in vivo; intercellular communication; knockout gene; monocyte; mouse model; prevent; primary endpoint; proliferative phase Menstrual cycle; recruit; rectal; reproductive function; reproductive tract; response; sex; single-cell RNA sequencing; stem; tissue resident memory T cell; urinary

ABSTRACT: Progesterone (P4) is a key sex hormone governing the physiological changes of the menstrual cycle. We and others have shown that it also has anti-inflammatory effects on the immune system locally in the female reproductive tract (FRT), but the mechanisms are not well understood. There are also indications that its immune effects reach beyond the FRT and affect immunity systemically. P4’s effects are likely modified by the more pro-inflammatory effects of estradiol (E2). A detailed understanding of the mechanisms behind P4’s immune activities at local and systemic sites, and its interactions with E2, may contribute to women’s health by explaining sex-based and menstrual cycle-related fluctuations in inflammatory diseases. Some inflammatory diseases fluctuate during the menstrual cycle, suggesting that P4 has systemic immune effects. For example, asthma and inflammatory bowel disease worsen in the P4-low follicular phase, while rheumatoid arthritis often improves in the P4-dominant luteal phase. On the other hand, P4-induced immunosuppression could limit the response to vaccination or resistance to infection. P4 surges during the luteal phase of the menstrual cycle, reaching >40 times above follicular phase levels. Our data show a clear immunological difference in the FRT between the phases: luteal inhibition of macrophage- tropic chemokines by P4. Monocytes/macrophages and dendritic cells (DC) are antigen-presenting cells (APC), which provide key signals for the localization and survival of resident memory T cells (TRM). We propose complementary human and mouse studies: (1) a human cohort with studies at the APC level, probing their connections to TRM in the FRT and other barrier sites and (2) mouse experiments to corroborate P4’s immunological properties in combination with E2 and to test the hypothesis that vaginal CCL2/CCL4 administration partially reverses P4-induced immune suppression. In Aim 1, we will recruit a clinical cohort to study the effects of the P4-dominant luteal phase in humans on APC and TRM activation and function in the FRT, the gastrointestinal tract, the upper respiratory tract, the skin, and the blood. We will use MSD-based immune factor profiling of secretions and flow cytometry and single cell RNA sequencing of mucosal cells to address three hypotheses: (1) inhibition of APC-tropic chemokine production is a hallmark of barrier site immunosuppression during the luteal phase; (2) mucosal APCs are fewer or less inflammatory during the luteal than the follicular phase; and (3) the APC and cytokine changes during the luteal phase associate with lower number and/or activation status of TRM. In Aim 2, we will use mouse models to establish a causal link between P4 treatment, chemokine production, and APC & TRM frequencies and activation state. We will address two hypotheses: (1) P4 inhibits production of CCL2 and CCL4 in major barrier tissues, reducing APC and TRM frequencies and/or functional potential; and (2) vaginal CCL2/4 administration prevents P4-induced suppression of APC and TRM.

摘要：孕激素（P4）是控制月经的生理变化的关键性激素 循环。我们和其他人表明，它还对当地的免疫系统具有抗炎作用 女性生殖道（FRT），但这些机制尚不清楚。也有迹象表明 它的免疫作用超出了FRT，并系统地影响免疫学。 P4的效果可能被修改 雌二醇的促炎作用（E2）。对背后机制的详细理解 P4在本地和系统网站的免疫活动及其与E2的互动可能有助于 通过解释炎症中基于性别和月经相关的波动，妇女的健康 疾病。一些炎症性疾病在月经周期中波动，表明P4具有 系统性免疫作用。例如，哮喘和炎症性肠病在P4-low中恶化 卵泡期，而类风湿关节炎通常在P4占主导地位的黄体期改善。另一方面， P4诱导的免疫抑制可能会限制对感染疫苗接种或抗性的反应。 在月经周期的黄体期间的P4涌入，高于卵泡相位的40倍。我们的 数据表明，阶段之间的FRT有明显的免疫学差异：巨噬细胞的黄体抑制 P4的热带趋化因子。单核细胞/巨噬细胞和树突状细胞（DC）是抗原呈递细胞 （APC），它为居民记忆T细胞（TRM）的定位和存活提供了关键信号。 我们提出了完整的人类和小鼠研究：（1）与APC水平研究的人类队列， 探测它们与FRT和其他屏障站点中的TRM的连接，以及（2）鼠标实验以证实 P4与E2结合使用的免疫学特性，并检验了阴道CCL2/CCL4的假设 给药部分逆转了P4诱导的免疫抑制。 在AIM 1中，我们将招募临床队列来研究P4占主导地位阶段对人类的影响 在FRT中的APC和TRM激活和功能上，胃肠道，上呼吸道， 皮肤和血液。我们将使用基于MSD的分泌物和流式细胞术的免疫功能分析以及 粘膜细胞的单细胞RNA测序以解决三个假设：（1）抑制APC - 热带 趋化因子的产生是在黄体期间屏障部位免疫抑制的标志。 （2）粘膜 在黄体期间，APC比卵泡相少或更少。 （3）APC和细胞因子 在黄体期间的变化与TRM的数量较低和/或激活状态相关。 在AIM 2中，我们将使用鼠标模型在P4处理，趋化因子之间建立因果关系 生产，APC和TRM频率和激活状态。我们将解决两个假设：（1）P4 抑制主要屏障组织中CCL2和CCL4的产生，降低APC和TRM频率和/或 功能潜力； （2）阴道CCL2/4给药可阻止P4诱导的APC和TRM抑制。