中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (5): 1084-1091.doi: 10.4103/1673-5374.382860

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

miR-9-5p/CXCL11通路是硫化氢拮抗缺氧缺血脑损伤神经炎症的关键靶点 

  

  • 出版日期:2024-05-15 发布日期:2023-10-31
  • 基金资助:
    国家自然科学基金项目（82271327，82072535，81873768，82001253）

The miR-9-5p/CXCL11 pathway is a key target of hydrogen sulfide-mediated inhibition of neuroinflammation in hypoxic ischemic brain injury 

Yijing Zhao1, #, Tong Li2, #, Zige Jiang1, Chengcheng Gai1, Shuwen Yu3, Danqing Xin1, Tingting Li1, Dexiang Liu3, *, Zhen Wang1, 4, *   

  1. 1Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China; 2Department of Neurosurgery, Qingdao Municipal Hospital, Qingdao, Shandong Province, China; 3Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China; 4Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province Affiliated to Qingdao University, Jinan, Shandong Province, China
  • Online:2024-05-15 Published:2023-10-31
  • Contact: Dexiang Liu, PhD, liudexiang@sdu.edu.cn; Zhen Wang, PhD, wangzhen@sdu.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 82271327 (to ZW), 82072535 (to ZW), 81873768 (to ZW), and 82001253 (to TL).

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摘要：

作者既往研究发现，硫化氢（H2S）对新生小鼠缺氧缺血脑损伤有神经保护作用。但是，目前尚不清楚硫化氢产生这种作用的具体机制。此次实验在缺氧缺血脑损伤新生小鼠模型以及脂多糖诱导的BV2细胞模型中证实，硫化氢的前体L-半胱氨酸治疗可减轻缺氧缺血诱导的脑梗死和脑萎缩，并增加前额叶皮质中miR-9-5p和胱硫氨酸β-合成酶（大脑中主要的硫化氢合成酶）的表达；且miR-9-5p抑制剂可阻断缺氧缺血脑损伤新生小鼠损伤前额叶皮质中胱硫氨酸β-合成酶的表达。而在缺氧缺血脑损伤新生小鼠损伤前额叶皮质中过表达miR-9-5p，可见胱硫氨酸β-合成酶表达和硫化氢合成增加。L-半胱氨酸还可降低缺氧缺血脑损伤小鼠前额叶皮质和脂多糖诱导的BV-2细胞中miR-9-5p的靶基因之一CXCL11的表达，并增加促炎细胞因子BNIP3，FSTL1，SOCS2以及SOCS5水平，而miR-9-5p抑制剂可逆转上述变化。由此提示，硫化氢可通过调节miR-9-5p/CXCL11轴对改善缺氧缺血脑损伤新生小鼠神经炎症，恢复胱硫氨酸β-合成酶表达，从而发挥减轻缺氧缺血脑损伤神经炎症的作用。

https://orcid.org/0000-0003-3173-6961 (Zhen Wang); https://orcid.org/0000-0001-5023-4874 (Dexiang Liu)

关键词: miR-9-5p, 硫化氢, 炎症, 小胶质细胞, 缺氧缺血脑损伤, L-半胱氨酸, 胱硫氨酸β-合成酶, 趋化因子(C-X-C基序)配体11, 神经保护, 脂多糖

Abstract: We previously showed that hydrogen sulfide (H2S) has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice. However, the precise mechanism underlying the role of H2S in this situation remains unclear. In this study, we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine, a H2S precursor, attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionine β synthase (a major H2S synthetase in the brain) in the prefrontal cortex. We also found that an miR-9-5p inhibitor blocked the expression of cystathionine β synthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia. Furthermore, miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury. L-cysteine decreased the expression of CXCL11, an miR-9-5p target gene, in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3, FSTL1, SOCS2 and SOCS5, while treatment with an miR-9-5p inhibitor reversed these changes. These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoring β-synthase expression, thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.  

Key words: chemokine (C-X-C motif) ligand 11, cystathionine β synthase, H2S, hypoxic ischemic brain injury, inflammation, L-cysteine, lipopolysaccharide, microglia, miR-9-5p, neuroprotection