Transcription factor <i>Dmrt1</i> triggers the SPRY1-NF-κB pathway to maintain testicular immune homeostasis and male fertility
Meng-Fei Zhang, 西北农林科技大学动物医学院, 陕西省干细胞工程技术中心, 陕西 杨凌 712100, 中国, Shicheng Wan, Wenbo Chen, Donghui Yang, Wenqing Liu, Balun Li, Aili Aierken, Xiaomin Du, Yunxiang Li, Wenping Wu, Xinchun Yang, Yudong Wei, Na Li, Sha Peng, Xueling Li, Guangpeng Li, Jinlian Hua, 阿姆斯特丹大学生殖医学中心, 阿姆斯特丹 1105AZ, 荷兰, 内蒙古大学教育部哺乳动物生殖生物学及生物技术重点实验室, 内蒙古 呼和浩特010021, 中国, 西北农林科技大学家畜生物学重点实验室, 陕西 杨凌712100, 中国
Abstract
Bacterial or viral infections, such as <i>Brucella</i>, 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 <i>Dmrt1</i> plays an important role in regulating testicular immune homeostasis. Knockdown of <i>Dmrt1</i> 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 <i>Dmrt1</i> positively regulated the expression of <i>Spry1</i>, 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 <i>Dmrt1</i>-<i>Spry1</i>-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.