Macrophage ubiquitin-specific protease 2 contributes to motility, hyperactivation, capacitation, and in vitro fertilization activity of mouse sperm
Macrophage ubiquitin-specific protease 2 contributes to motility, hyperactivation, capacitation, and in vitro fertilization activity of mouse sperm
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DOI：
10.1007/s00018-020-03683-9
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发表时间：
2020-10-26
影响因子：
8
通讯作者：
Kitamura, Hiroshi
中科院分区：
文献类型：
--
作者：
Hashimoto, Mayuko;Kimura, Shunsuke;Kitamura, Hiroshi
巨噬细胞是先天性免疫细胞，有助于经典的免疫功能和组织稳态。泛素特异性蛋白酶2（USP 2）控制巨噬细胞中细胞因子的产生，但其器官特异性作用仍然未知。在这项研究中，我们产生了骨髓选择性Usp 2敲除（msUsp 2KO）小鼠，并专门探讨了睾丸巨噬细胞衍生的USP 2在生殖中的作用。msUsp 2KO小鼠在各种组织中表现出正常的巨噬细胞特征。在睾丸中，巨噬细胞Usp 2缺陷对睾丸巨噬细胞亚群、精子发生和睾丸器官发生的影响可忽略不计。然而，来自msUsp 2KO小鼠的冷冻-解冻精子表现出运动性、获能和超活化降低。此外，巨噬细胞Usp 2消融导致精子数量减少，表现出高细胞内pH值、钙内流和线粒体膜电位。当使用来自msUsp 2KO小鼠的冻融精子进行体外受精时，观察到卵中原核形成中断。粒细胞巨噬细胞集落刺激因子（GM-CSF）的管理，其表达减少来自msUsp 2KO小鼠的睾丸巨噬细胞，恢复线粒体膜电位和总精子活力。我们的观察表明，去泛素化酶在器官特异性巨噬细胞中的独特作用，直接影响精子功能。
Macrophages are innate immune cells that contribute to classical immune functions and tissue homeostasis. Ubiquitin-specific protease 2 (USP2) controls cytokine production in macrophages, but its organ-specific roles are still unknown. In this study, we generated myeloid-selective Usp2 knockout (msUsp2KO) mice and specifically explored the roles of testicular macrophage-derived USP2 in reproduction. The msUsp2KO mice exhibited normal macrophage characteristics in various tissues. In the testis, macrophage Usp2 deficiency negligibly affected testicular macrophage subpopulations, spermatogenesis, and testicular organogenesis. However, frozen-thawed sperm derived from msUsp2KO mice exhibited reduced motility, capacitation, and hyperactivation. In addition, macrophage Usp2 ablation led to a decrease in the sperm population exhibiting high intracellular pH, calcium influx, and mitochondrial membrane potential. Interrupted pronuclei formation in eggs was observed when using frozen-thawed sperm from msUsp2KO mice for in vitro fertilization. Administration of granulocyte macrophage-colony stimulating factor (GM-CSF), whose expression was decreased in testicular macrophages derived from msUsp2KO mice, restored mitochondrial membrane potential and total sperm motility. Our observations demonstrate a distinct role of the deubiquitinating enzyme in organ-specific macrophages that directly affect sperm function.