TRIM27在脑缺血再灌注损伤中通过TBK1依赖性自噬促进小胶质细胞M2极化和神经保护
TRIM27 promotes microglial M2 polarization and neuroprotection via TBK1-dependent autophagy in cerebral ischemia-reperfusion injury.
摘要(中文译文)
小胶质细胞激活和功能障碍在缺血性脑卒中的发病机制中发挥关键作用，然而调控其表型可塑性和保护功能的分子机制仍不完全清楚。在此，我们整合转录组学分析与功能验证，鉴定出TRIM27是脑缺血再灌注损伤后小胶质细胞自噬和极化的一种新型调控因子。对接受大脑中动脉闭塞（MCAO）小鼠分离的CD11b小胶质细胞进行RNA测序，发现Trim27显著下调，且与自噬通路受损相关。通过AAV9递送在体内过表达TRIM27可显著减轻MCAO后的梗死体积、神经元变性和凋亡。这种神经保护作用伴随小胶质细胞表型从促炎M1状态向抗炎M2状态转变，以及自噬流增强。在体外，对氧糖剥夺/复氧（OGD/R）处理的小胶质细胞过表达TRIM27可抑制线粒体活性氧产生和脂质过氧化，提高细胞存活率。在机制上，TRIM27与TANK结合激酶1（TBK1）发生物理相互作用，并通过抑制其泛素介导的降解来稳定TBK1。值得注意的是，Tbk1基因敲除在体内和体外均消除了TRIM27对小胶质细胞极化、自噬、氧化应激和神经保护的有益效应。我们的研究确立了TRIM27-TBK1轴是缺血性脑卒中小胶质细胞功能的关键调控因子，突显其作为通过自噬依赖性免疫调节促进脑修复的治疗靶点的潜力。
Abstract
Microglial activation and dysfunction play pivotal roles in the pathogenesis of ischemic stroke, yet the molecular mechanisms governing their phenotypic plasticity and protective functions remain incompletely understood. Here, we integrated transcriptomic profiling with functional validation to identify TRIM27 as a novel regulator of microglial autophagy and polarization following cerebral ischemia-reperfusion injury. RNA sequencing of CD11b microglia isolated from mice subjected to middle cerebral artery occlusion (MCAO) revealed significant downregulation of Trim27, which was associated with impaired autophagy pathways. In vivo overexpression of TRIM27 via AAV9 delivery markedly attenuated infarct volume, neuronal degeneration, and apoptosis after MCAO. This neuroprotection was accompanied by a shift in microglial phenotype from pro-inflammatory M1 toward anti-inflammatory M2 states, along with enhanced autophagic flux. In vitro, TRIM27 overexpression in oxygen-glucose deprivation/reoxygenation (OGD/R)-treated microglia suppressed mitochondrial reactive oxygen species production and lipid peroxidation, improving cell survival. Mechanistically, TRIM27 physically interacted with and stabilized TANK-binding kinase 1 (TBK1) by inhibiting its ubiquitin-mediated degradation. Notably, genetic ablation of Tbk1 abolished the beneficial effects of TRIM27 on microglial polarization, autophagy, oxidative stress, and neuroprotection both in vivo and in vitro. Our findings establish a TRIM27-TBK1 axis as a critical modulator of microglial function in ischemic stroke, highlighting its potential as a therapeutic target for promoting brain repair through autophagy-dependent immunomodulation.
如何引用
AMA
Dujie Xie, Shunbing Hu, Panyao Long, Juan Huang, Xiaobo Li, Yi Yuan, et al. TRIM27 promotes microglial M2 polarization and neuroprotection via TBK1-dependent autophagy in cerebral ischemia-reperfusion injury.. International immunopharmacology. 2026; doi:10.1016/j.intimp.2026.116597.
APA
Dujie Xie, Shunbing Hu, Panyao Long, Juan Huang, Xiaobo Li, Yi Yuan, et al (2026). TRIM27 promotes microglial M2 polarization and neuroprotection via TBK1-dependent autophagy in cerebral ischemia-reperfusion injury.. International immunopharmacology. https://doi.org/10.1016/j.intimp.2026.116597
GB/T 7714
Dujie Xie, Shunbing Hu, Panyao Long, Juan Huang, Xiaobo Li, Yi Yuan, et al. TRIM27 promotes microglial M2 polarization and neuroprotection via TBK1-dependent autophagy in cerebral ischemia-reperfusion injury.[J]. International immunopharmacology, 2026 doi:10.1016/j.intimp.2026.116597.
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