HDAC 5抑制睾丸巨噬细胞M1极化增强对LPS引起的血-睾丸屏障损伤的不敏感性

Suppressed testicular macrophage M1 polarization by HDAC5 enforces insensitivity to LPS-elicited blood-testis barrier damage  

HDAC 5抑制睾丸巨噬细胞M1极化增强对LPS引起的血-睾丸屏障损伤的不敏感性

Authors: Li H, Hu YF, Wang XR, Ouyang KW, Wang H, Wang KW, Chang W, Zhang J, Yuan Z, Xiong YW, Zhu HL, Yang L, Wang H.

Source：Food Chem Toxicol. 2024 Aug 14;192:114940. doi: 10.1016/j.fct.2024.114940.

Abstract

Infertility caused by lipopolysaccharide (LPS) exposure due to infection is endangering male fertility worldwide, but the mechanism remains unclear. The blood-testis barrier (BTB) is essential for maintaining spermatogenesis and male fertility. In the present study, we showed that LPS (5.0 mg/kg) treatment markedly down-regulated the expression of BTB-related proteins, expanded the biotin penetration distance and caused histopathological injury in seminiferous tubules in mouse testes. Notably, testicular macrophage M1 polarization induced by LPS seems to be related to BTB damage, which was well confirmed by co-culture of RAW264.7 and TM4 cells in vitro. Interestingly, a low-dose LPS (0.1 mg/kg) pretreatment attenuated down-regulation of BTB-related proteins expression and histopathological injury and shorten biotin penetration distance in seminiferous tubules caused by LPS. Correspondingly, a low-dose LPS pretreatment suppresses testicular macrophage M1 polarization induced by LPS in mouse testes. Further experiments revealed that histone deacetylase 5 (HDAC5) was markedly down-regulated at 2 h and slightly down-regulated at 8 h, but up-regulated at 24 h in mouse testes after LPS treatment. Additionally, low-dose LPS pretreatment against the down-regulation of HDAC5 protein caused by LPS treatment. Notably, the suppressed testicular macrophage M1 polarization by low-dose LPS pretreatment was broken by BRD4354, a specific inhibitor of HDAC5 in vitro. These results suggest suppressed testicular macrophage M1 polarization by HDAC5 enforces insensitivity to LPS-elicited BTB damage.

Keywords: Blood-testis barrier; HDAC; LPS tolerance; M1/M2 polarization; Macrophage; Male reproduction toxicity.

摘要

由于感染引起的脂多糖（LPS）暴露引起的不育正在危及全球男性生育能力，但其机制仍不清楚。血睾屏障（BTB）对维持精子发生和男性生育力至关重要。在本研究中，我们发现，LPS（5.0 mg/kg）治疗显着下调BTB相关蛋白的表达，扩大生物素渗透距离，并造成组织病理学损伤的曲细精管在小鼠睾丸。值得注意的是，LPS诱导的睾丸巨噬细胞M1极化似乎与BTB损伤有关，这在体外RAW 264.7和TM 4细胞的共培养中得到了很好的证实。有趣的是，低剂量LPS（0.1 mg/kg）预处理减弱了LPS引起的BTB相关蛋白表达的下调和组织病理学损伤，并缩短了生精小管中生物素的穿透距离。相应地，低剂量LPS预处理抑制小鼠睾丸中LPS诱导的睾丸巨噬细胞M1极化。进一步的实验表明，组蛋白去乙酰化酶5（HDAC 5）在LPS处理后2 h显著下调，8 h略有下调，但在24 h上调。低剂量LPS预处理可对抗LPS引起的HDAC 5蛋白表达下调。值得注意的是，低剂量LPS预处理抑制的睾丸巨噬细胞M1极化被体外HDAC 5特异性抑制剂BRD 4354打破。这些结果表明，HDAC 5抑制睾丸巨噬细胞M1极化，使其对LPS引起的BTB损伤不敏感。

关键词：血睾屏障; HDAC; LPS耐受; M1/M2极化;巨噬细胞;雄性生殖毒性