Figueiredo A F A, Wnuk N T, Vieira C P, Gonçalves M F F, Brener M R G, Diniz A B, Antunes M M, Castro-Oliveira H M, Menezes G B, Costa G M J
Laboratory of Cellular Biology, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
Center for Gastrointestinal Biology, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
Cell Tissue Res. 2021 Oct;386(1):173-190. doi: 10.1007/s00441-021-03504-w. Epub 2021 Jul 23.
The monocyte chemoattractant protein 1 (MCP-1) belongs to the CC chemokine family and acts in the recruitment of C-C motif chemokine receptor 2 (CCR2)-positive immune cell types to inflammation sites. In testis, the MCP-1/CCR2 axis has been associated with the macrophage population's functional regulation, which presents significant functions supporting germ cell development. In this context, herein, we aimed to investigate the role of the chemokine receptor CCR2 in mice testicular environment and its impact on male sperm production. Using adult transgenic mice strain that had the CCR2 gene replaced by a red fluorescent protein gene, we showed a stage-dependent expression of CCR2 in type B spermatogonia and early primary spermatocytes. Several parameters related to sperm production were reduced in the absence of CCR2 protein, such as Sertoli cell efficiency, meiotic index, and overall yield of spermatogenesis. Daily sperm production decreased by almost 40%, and several damages in the seminiferous tubules were observed. Significant reduction in the expression of important genes related to the Sertoli cell function (Cnx43, Vim, Ocln, Spna2) and meiosis initiation (Stra8, Pcna, Prdm9, Msh5) occurred in comparison to controls. Also, the number of macrophages significantly decreased in the absence of CCR2 protein, along with a disturbance in Leydig cell steroidogenic activity. In summary, our results show that the non-activation of the MCP-1/CCR2 axis disturbs the testicular homeostasis, interfering in macrophage population, meiosis initiation, blood-testis barrier function, and androgen synthesis, leading to the malfunction of seminiferous tubules, decreased testosterone levels, defective sperm production, and lower fertility index.
单核细胞趋化蛋白1（MCP-1）属于CC趋化因子家族，作用是将C-C基序趋化因子受体2（CCR2）阳性免疫细胞类型招募到炎症部位。在睾丸中，MCP-1/CCR2轴与巨噬细胞群体的功能调节有关，巨噬细胞群体对支持生殖细胞发育具有重要作用。在此背景下，我们旨在研究趋化因子受体CCR2在小鼠睾丸环境中的作用及其对雄性精子生成的影响。使用成年转基因小鼠品系，其CCR2基因被红色荧光蛋白基因取代，我们发现CCR2在B型精原细胞和早期初级精母细胞中呈阶段依赖性表达。在缺乏CCR2蛋白的情况下，与精子生成相关的几个参数降低，如支持细胞效率、减数分裂指数和精子发生的总体产量。每日精子产量下降近40%，并观察到生精小管的一些损伤。与对照组相比，与支持细胞功能（Cnx43、Vim、Ocln、Spna2）和减数分裂起始（Stra8、Pcna、Prdm9、Msh5）相关的重要基因表达显著降低。此外，在缺乏CCR2蛋白的情况下，巨噬细胞数量显著减少，同时睾丸间质细胞类固醇生成活性受到干扰。总之，我们的结果表明，MCP-1/CCR2轴未激活会扰乱睾丸内环境稳定，干扰巨噬细胞群体、减数分裂起始、血睾屏障功能和雄激素合成，导致生精小管功能障碍、睾酮水平降低、精子生成缺陷和生育指数降低。
