Bacterial or viral infections, such as Brucella, mumps virus, herpes simplex virus, and Zika virus, destroy immune homeostasis of the testes, leading to spermatogenesis disorder and infertility. Of note, recent research shows that SARS-CoV-2 can infect male gonads and destroy Sertoli and Leydig cells, leading to male reproductive dysfunction. Due to the many side effects associated with antibiotic therapy, finding alternative treatments for inflammatory injury remains critical. Here, we found that Dmrt1 plays an important role in regulating testicular immune homeostasis. Knockdown of Dmrt1 in male mice inhibited spermatogenesis with a broad inflammatory response in seminiferous tubules and led to the loss of spermatogenic epithelial cells. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed that Dmrt1 positively regulated the expression of Spry1, an inhibitory protein of the receptor tyrosine kinase (RTK) signaling pathway. Furthermore, immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) analysis indicated that SPRY1 binds to nuclear factor kappa B1 (NF-κB1) to prevent nuclear translocation of p65, inhibit activation of NF-κB signaling, prevent excessive inflammatory reaction in the testis, and protect the integrity of the blood-testis barrier. In view of this newly identified Dmrt1- Spry1-NF-κB axis mechanism in the regulation of testicular immune homeostasis, our study opens new avenues for the prevention and treatment of male reproductive diseases in humans and livestock.
细菌或病毒感染会破坏睾丸的免疫稳态，如布鲁氏菌、腮腺炎病毒、单纯疱疹病毒和寨卡病毒，都会导致精子发生障碍和不育。最新研究表明，SARS-CoV-2可感染男性性腺，破坏支持细胞和间质细胞，并导致男性生殖功能障碍。由于抗生素治疗的局限性，迫切需要探寻生殖系统炎症的替代治疗方法。在该研究中，我们发现 Dmrt1在调节睾丸免疫稳态中发挥着重要作用。 Dmrt1缺陷小鼠的生精能力降低，曲细精小管中存在广泛的炎症反应，导致生精上皮细胞的脱落和丢失。ChIP-seq和RNA-seq分析表明， Dmrt1直接调节许多与炎症途径相关的基因且正向调控 Spry1的表达。在用脂多糖（LPS）刺激后，睾丸中 Dmrt1或 Spry1的敲除都导致更严重的炎症反应、BTB损伤和NF-κB信号的激活。IP-MS和Co-IP结果表明，SPRY1蛋白与NF-κB1结合，从而抑制NF-κB通路的激活，防止睾丸过度炎症反应，并保护血-睾屏障的完整性。该研究发现了Dmrt1-Spry1-NF-κB轴在调节睾丸免疫稳态中的新机制，为预防、治疗人类和家畜的生殖系统疾病开辟了新的途径。.
Keywords: Dmrt1; NF-κB; Orchitis; Spermatogenesis; Spry1.