Gao Feng, Zheng Zijian, Liu Xinjie, Li Jianwei
Department of Neurosurgery, Xingtai People's Hospital, Xingtai, Hebei, China.
Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
Sci Rep. 2025 Apr 7;15(1):11807. doi: 10.1038/s41598-025-97232-8.
The activation of microglia and the resulting neuroinflammation play crucial regulatory roles in the pathogenesis and progression of neurological diseases, although the specific mechanisms remain incompletely understood. Cytidine monophosphate kinase 2 (CMPK2) is a key mitochondrial nucleotide kinase involved in cellular energy metabolism and nucleotide synthesis. Recent studies suggest that CMPK2 plays a role in microglial-mediated neuroinflammation; however, its specific impact on microglial activation remains unclear. In this study, we hypothesize that CMPK2 promotes microglial-mediated neuroinflammation by activating the cGAS-STING signaling pathway. To investigate this mechanism, we employed lipopolysaccharide (LPS)-treated microglial cells to investigate the detailed mechanisms by which CMPK2 regulates neuroinflammation. Our experimental results indicate that in the BV2 and mouse primary microglial neuroinflammation model, both CMPK2 protein and transcript levels were significantly elevated, accompanied by microglial activation phenotypes such as increased cell size, shortened processes, transformation to round or rod-like shapes, and elevated CD40 expression. Concurrently, there was an increase in pro-inflammatory cytokine levels and a decrease in anti-inflammatory cytokine levels. Further investigation revealed that in the microglial, the expression of cGAS and STING was elevated, along with an increase in oxidative products and inflammatory responses. CMA stimulation further intensified these changes, while cGAS knockdown mitigated them. Finally, we demonstrated that cGAS knockdown inhibited the oxidative stress, cell activation-related changes, and neuroinflammatory responses induced by CMPK2 overexpression in the BV2 neuroinflammation model. Molecular docking experiments showed that CMPK2 stably binds to cGAS at the protein level. These findings suggest that the cGAS-STING pathway mediates CMPK2-induced microglial activation. In summary, our study demonstrates that LPS-induced CMPK2 overactivity promotes microglial activation and neuroinflammatory through the cGAS-STING pathway.
小胶质细胞的激活及由此产生的神经炎症在神经疾病的发病机制和进展中发挥着关键的调节作用，尽管其具体机制仍未完全明确。胞苷单磷酸激酶2（CMPK2）是一种参与细胞能量代谢和核苷酸合成的关键线粒体核苷酸激酶。最近的研究表明，CMPK2在小胶质细胞介导的神经炎症中发挥作用；然而，其对小胶质细胞激活的具体影响仍不清楚。在本研究中，我们假设CMPK2通过激活cGAS-STING信号通路促进小胶质细胞介导的神经炎症。为了探究这一机制，我们使用脂多糖（LPS）处理的小胶质细胞来研究CMPK2调节神经炎症的详细机制。我们的实验结果表明，在BV2和小鼠原代小胶质细胞神经炎症模型中，CMPK2蛋白和转录水平均显著升高，同时伴有小胶质细胞激活表型，如细胞大小增加、突起缩短、转变为圆形或杆状形状以及CD40表达升高。同时，促炎细胞因子水平升高，抗炎细胞因子水平降低。进一步研究发现，在小胶质细胞中，cGAS和STING的表达升高，同时氧化产物和炎症反应增加。CMA刺激进一步加剧了这些变化，而cGAS敲低则减轻了这些变化。最后，我们证明cGAS敲低抑制了BV2神经炎症模型中CMPK2过表达诱导的氧化应激、细胞激活相关变化和神经炎症反应。分子对接实验表明，CMPK2在蛋白水平上与cGAS稳定结合。这些发现表明，cGAS-STING通路介导了CMPK2诱导的小胶质细胞激活。总之，我们的研究表明，LPS诱导的CMPK2过度活化通过cGAS-STING通路促进小胶质细胞激活和神经炎症。
