Guo Yanan, Xia Peng, Tian Yixiao, Fu Daosen, Hu Xiaohui, Xie Kun, Dong Wenhao, Zhang Wei, Liu Disheng, Shen Rong, Wang Degui
School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China.
Reproductive Medicine Center, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu, China.
Cell Death Discov. 2025 Jul 24;11(1):339. doi: 10.1038/s41420-025-02641-3.
Dysregulated immune responses may erroneously target normal reproductive tissues, thereby compromising the proper functioning of the reproductive system. Macrophages are the most abundant immune cells in the testes, however, the role of macrophages in spermatogenic function is not yet clear. This study indicated that the increase of pro-inflammatory macrophages impaired the development of spermatogenic cells, and the deficiency of RNF8 led to a proinflammatory state in the testicular microenvironment and diminished sperm production in mice. RNF8 mainly assembled K63-branched ubiquitin chains on autophagy receptor OPTN at K448 thus causing OPTN activation. The increased ubiquitination of OPTN promoted degradation of KDM6A via the autophagy-lysosome pathway, thereby inhibiting macrophage polarization towards the pro-inflammatory type and maintaining an immune privilege state in the testicular microenvironment. This homeostasis could be collapsed once the RNF8-OPTN-KDM6A axis was abnormal, subsequently resulting in remodeling of the testicular microenvironment. This study reveals the underlying mechanism of RNF8 on male reproduction, and the pro-inflammatory microenvironment resulting from RNF8 deficiency hindered spermatogenic cell differentiation, thereby impairing spermatogenic function.
免疫反应失调可能错误地靶向正常生殖组织，从而损害生殖系统的正常功能。巨噬细胞是睾丸中最丰富的免疫细胞，然而，巨噬细胞在生精功能中的作用尚不清楚。本研究表明，促炎性巨噬细胞的增加会损害生精细胞的发育，而RNF8的缺乏会导致睾丸微环境处于促炎状态，并减少小鼠的精子产生。RNF8主要在自噬受体OPTN的K448位点组装K63分支的泛素链，从而导致OPTN激活。OPTN泛素化增加通过自噬-溶酶体途径促进KDM6A的降解，从而抑制巨噬细胞向促炎型极化，并在睾丸微环境中维持免疫特权状态。一旦RNF8-OPTN-KDM6A轴异常，这种稳态就会被打破，随后导致睾丸微环境重塑。本研究揭示了RNF8对雄性生殖的潜在机制，RNF8缺乏导致的促炎微环境阻碍了生精细胞分化，从而损害了生精功能。
