睾丸免疫环境与睾丸炎的调节机理

Mammalian testis poses a special immunological environment considering that the immunogenic germ cells can be protected from immune system attack, termed immune privilege. However, efficient local innate immune responses against invading pathogens are mounted in the testis to overcome the immune privilege. Impaired immune homeostasis of the testis may lead to orchitis, which is one of etiological factors of male infertility. The regulation of testicular immunity is an important issue in the field of reproductive biology. This proposal will investigate the interplay of pattern recognition receptors (PRRs) and TAM (Tyro3, Axl, and Mer) receptor tyrosine kinases in regulating testicular innate immune response and orchitis. Three specific aims will be focused in this proposal: (1) To examine PRR-mediated innate immune response in testicular cells, including roles of Toll-like receptors (TLRs), RIG-I-like receptors (NLR), and NOD-like receptors (NLRs) in regulating testicular innate immunity; (2) To understand roles of the PRRs in controlling orchitis caused by invading pathogens and auto-antigens. In particularly, the study will focus on the regulation of autoimmune orchitis by TLR activation. (3) To reveal roles of TAM receptors in maintaining testicular immune homeostasis by inhibiting PRR-mediated innate immune response. This proposal is important since it aims to answer an open question in the field regarding regulation of the specific immune environment in the testis. Outcomes of the proposed studies will further understand the mechanisms underlying the testicular immune regulation and orchitis, which may provide novel clues into the preventive and therapeutic strategies for orchitis-related male infertility.

哺乳动物睾丸具有特殊的免疫环境，既要保护生殖细胞不受免疫系统的损伤（即免疫豁免），又建立了局部有效的天然免疫机制抵御入侵的病原体。睾丸免疫稳态失衡可导致睾丸炎，是男性不育的重要病因之一，其调节机理是生殖生物学领域广泛关注的科学问题。本项目利用小鼠为模型，拟研究模式识别受体（PRR）介导的睾丸天然免疫反应与睾丸炎的关系。主要内容包括：（1）Toll-样受体（TLR）、RIG-I样受体（RLR）与NOD样受体（NLR）在介导睾丸细胞天然免疫反应中的功能；（2）睾丸细胞的天然免疫反应与感染及自身免疫睾丸炎的关系，着重于TLR对自身免疫睾丸炎的调节作用；（3）TAM (Tyro3, Axl and Mer）受体在维持睾丸免疫平衡中的功能，重点分析TAM抑制睾丸细胞天然免疫反应的机理。目的是进一步揭示维持睾丸免疫稳态及睾丸炎产生的分子机理，认识关键调控环节，为预防及治疗睾丸炎引起的男性不育提供线索。

本课题旨在研究睾丸免疫豁免环境与睾丸炎相关的调节机制，顺利完成了预期的任务。主要在以下四个方面取得了新的进展：1.TLR介导的睾丸及附睾天然免疫反应。发现多个TLR表达于不同的小鼠睾丸细胞及附睾上皮细胞中，上述受体皆可启动天然免疫反应并在睾丸及附睾抵抗感染病原体反应中具有重要意义。2.TAM 受体酪氨酸激酶在维持睾丸免疫稳态中的功能。TAM受体通过调节Sertoli细胞的功能在维持睾丸免疫稳态中起重要作用，敲除TAM可导致自发性慢性睾丸炎，精子发生受损，从而影响雄性小鼠的生育力。3.TLR及TAM受体酪氨酸激酶在调节小鼠实验性自身免疫睾丸炎中的功能。研究发现TLR2和TLR4共同作用，参与调节EAO的产生，并且TLR2与针对生精细胞自身抗原的抗体产生相关。另外Axl和Mer两个受体酪氨酸激酶共同作用抑制小鼠EAO的产生，说明Axl和Mer参与维持针对生精细胞抗原的免疫耐受。这种抑制作用可能是通过抑制TLR2和TLR4信号通路实现的，对理解睾丸免疫豁免提供了新线索。4.核酸感受器介导睾丸及附睾天然免疫反应，研究发现睾丸Leydig细胞及附睾上皮细胞表达多种核酸感受器，包括RIG-I样受体（RIG-I和MDA5）及P204、cGAS和DAI等DNA感受器，相应感受器能够通过NF-κB及IRF-3信号通路激活炎症因子及1型干扰素的表达继而影响其生理功能。值得注意的是，RNA感受器诱导的天然免疫反应倾向于表达较高的炎症因子及较低的1型干扰素，而DNA感受器诱导的天然免疫反应正好相反。提示DNA病毒及RNA病毒诱导的天然免疫反应存在明显的差异。以上结果从多个方面证明睾丸免疫环境能够有效调节睾丸炎的形成。共发表相关论文21篇，其中SCI论文16篇，影响因子均大于3。待发表SCI论文2篇，影响因子均大于3。