Proton-secreting epithelial cells as key modulators of epididymal mucosal immunity.

分泌质子的上皮细胞是附睾粘膜免疫的关键调节剂。

基本信息

批准号：
10181353
负责人：
Maria Agustina Battistone
金额：
$ 35.12万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10181353
关键词：
3-Dimensional Ablation Address Animals Antigens Autoimmune Autoimmune Responses Autoimmunity Bacterial Antigens Bioinformatics Biology CX3CL1 gene CXCL10 gene Cell Communication Cell Separation Cells Clear Cell Communication Confocal Microscopy Data Development Diphtheria Toxin Disease Duct (organ) structure Environment Epididymis Epididymitis Epithelial Epithelial Cells Equilibrium FOXP3 gene Flow Cytometry Genes Goals Health Immune Immune Tolerance Immune response Immune system Immunology Infection Inflammation Inflammatory Response Injections Injury Knowledge Laboratory Study Ligands Maintenance Male Contraceptive Agents Male Infertility Mediator of activation protein Mission Mononuclear Mucosal Immunity Mucous Membrane Mus Neutrophil Infiltration Partner in relationship Pathogenicity Pathway interactions Phagocytes Play Positioning Attribute Protons Public Health Regulatory T-Lymphocyte Reproductive Biology Reproductive Health Reproductive Physiology Research Role Specialized Epithelial Cell Sperm Maturation Spermatic Cord Torsion Sterility Structure of thyroid parafollicular cell Surveys System Techniques Testis Torsion Transforming Growth Factor beta Transgenic Mice Tryptophan 2,3 Dioxygenase Tube Tubular formation United States National Institutes of Health Work base cell injury cell motility cell type chemokine human male immune activation immunoregulation innovation insight interdisciplinary approach macrophage male microorganism monocyte mouse model novel novel therapeutics pathogen prevent receptor recruit response sperm cell stressor transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT One of the most intriguing and understudied aspects of male reproductive physiology is the ability of the epididymis to prevent the development of immune responses against autoantigenic spermatozoa, while initiating very efficient immune responses against pathogens. The long-term goal of this application is to develop new strategic therapies for common disorders such as male infertility and epididymitis, and to identify novel targets for male-contraception. The overall objective is to elucidate how epididymal epithelial clear cells (CCs) communicate with immunocytes to contribute to the “immune privileged” environment that is optimal for sperm maturation and storage. We have recently showed a completely novel role for CCs in immune activation and sperm tolerance. Importantly, these cells establish intimate contact with region-specific heterogeneous subsets of mononuclear phagocytes (MPs) in the epididymis. Our central hypothesis is that CCs are strategically positioned to work in a concerted manner with immune cells to survey the epididymis barrier and regulate the balance between inflammation and immune tolerance in the post-testicular environment. The rationale is based on our preliminary data showing that CCs and MPs communicate in the steady state epididymis and also in the presence of infection or injury, and that both cell types express different tolerogenic mediators allowing the modulation of sperm tolerance. Therefore, these cells play a central role in the epididymal mucosa. In the first specific aim, we will determine CC – MP communication networks that initiate immune activation during epididymitis. In this aim, two mouse models of epididymitis will be used: injection of bacterial antigens into the cauda lumen, and epididymal-testicular torsion that induces sterile inflammation. In the second specific aim, we will evaluate CC - MP crosstalk after ablation of sperm tolerance in the epididymis, induced by depletion of regulatory T cells using diphtheria toxin-based transgenic mice. The research proposed in this application will use an innovative multidisciplinary approach that employs powerful immunology techniques rarely used to study reproductive physiology, 3D confocal microscopy, transcriptomics analysis, flow cytometry, cell sorting and bioinformatic analysis, as well as the use of mouse models to describe how specialized epithelial cells and immunocytes communicate in the epididymis. Notably, we will provide an in- depth characterization of three specific epididymal cell types: CCs and two subsets of MPs. Our proposed research is significant because it is expected to provide new insights into major immunoregulatory mechanisms by which epididymal CCs together with MPs protect spermatozoa against harmful antigens and autoimmunity. Ultimately, such knowledge will fill important gaps related to male reproductive biology by addressing crucial concepts of mucosal immunology and cell– cell interactions, all of which are critical but understudied facets of human male reproductive health.

项目概要/摘要男性生殖生理学最有趣和研究不足的方面之一是附睾的能力防止针对自身抗原精子的免疫反应的发展，同时启动非常有效的免疫该应用的长期目标是开发针对常见病原体的新战略疗法。男性不育症和附睾炎等疾病，并确定男性避孕的新目标。目的是阐明附睾上皮透明细胞（CC）如何与免疫细胞通讯以促进我们最近展示了一种最适合精子成熟和储存的“免疫特权”环境。 CC 在免疫激活和精子耐受性中发挥着全新的作用，重要的是，这些细胞建立了亲密的关系。与附睾中特定区域的异质单核吞噬细胞（MP）亚群接触。假设 CC 的战略定位是与免疫细胞协同工作来调查附睾屏障并调节睾丸后炎症和免疫耐受之间的平衡其基本原理基于我们的初步数据，表明 CC 和 MP 在稳定状态下进行通信。附睾以及存在感染或损伤的情况下，并且两种细胞类型表达不同的耐受性介质因此，这些细胞在附睾粘膜中发挥着核心作用。第一个具体目标是，我们将确定在附睾炎期间启动免疫激活的 CC-MP 通信网络。为此，将使用两种附睾炎小鼠模型：将细菌抗原注射到尾腔中，以及引起无菌性炎症的附睾睾丸扭转在第二个具体目标中，我们将评估 CC - MP。使用白喉消耗调节性 T 细胞诱导附睾中精子耐受性消融后的串扰本申请中提出的基于毒素的转基因小鼠的研究将采用创新的多学科方法。采用很少用于研究生殖生理学的强大免疫学技术、3D 共聚焦显微镜、转录组学分析、流式细胞术、细胞分选和生物信息学分析，以及使用小鼠模型来描述特化的上皮细胞和免疫细胞如何在附睾中进行交流值得注意的是，我们将提供一个内部信息。我们提出的研究是三种特定附睾细胞类型的深度表征：CC 和 MP 的两个子集。意义重大，因为它有望为附睾的主要免疫调节机制提供新的见解。 CC 与 MP 一起保护精子免受有害抗原和自身免疫的侵害。通过解决粘膜免疫学和细胞的关键概念，填补与男性生殖生物学相关的重要空白细胞相互作用，所有这些都是人类男性生殖健康的关键但尚未得到充分研究的方面。