Jiang Wenwen, Fan Xixin, Wu Hui, Song Jiankang, Yang Chunhe, Zhao Zhanzhi
Department of Anesthesiology, Panjin Liao-Oil Field Gem Flower Hospital, Panjin, Liaoning, China.
Department of Anesthesiology, Panjin Liao-Oil Field Gem Flower Hospital, Panjin, Liaoning, China.
Neurotoxicol Teratol. 2025 Jul-Aug;110:107500. doi: 10.1016/j.ntt.2025.107500. Epub 2025 May 31.
Neuroinflammation is a critical factor in the pathogenesis of postoperative cognitive dysfunction (POCD). Maintaining microglial homeostasis is vital for regulating neuroinflammation, as microglial cell death can trigger an inflammatory response within the central nervous system. The triggering receptor expressed on myeloid cells 2 (TREM2) plays an essential role in supporting cell survival and modulating microglial-driven neuroinflammation. Our previous study indicated that TREM2 overexpression exerts protective effects against neuroinflammation and cognitive deficits in aged mice. However, the precise mechanisms by which TREM2 functions in microglia remain unclear. Consequently, this study aimed to examine the role of TREM2 in lipopolysaccharide (LPS)-induced cell death and neuroinflammation in BV2 cells. This research showed that TREM2 reduces LPS-induced nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-mediated pyroptosis and the subsequent release of inflammatory factors through western blot analysis, flow cytometry, and enzyme-linked immunosorbent assay. Recent research has suggested that the loss of spleen tyrosine kinase (SYK), a downstream receptor kinase of TREM2 in microglia, results in exacerbated neuroinflammatory disease. This study further demonstrated that SYK activation via TREM2 treatment exerts neuroprotective effects by mitigating LPS-induced mitochondrial membrane potential damage, facilitating mitophagy, and inhibiting NLRP3-mediated pyroptosis in BV2 cells. Conversely, SYK inhibition by R406 led to microglial cell death and aggravated neuroinflammation, thereby reducing the neuroprotective effects of TREM2. Our findings indicate that TREM2 and SYK mitigate the inflammatory response in LPS-induced BV2 microglia and interfere with pyroptosis by enhancing mitophagy. These findings suggest that TREM2 and SYK may be valuable therapeutic targets for neuroinflammation.
神经炎症是术后认知功能障碍（POCD）发病机制中的关键因素。维持小胶质细胞的稳态对于调节神经炎症至关重要，因为小胶质细胞死亡会触发中枢神经系统内的炎症反应。髓系细胞触发受体2（TREM2）在支持细胞存活和调节小胶质细胞驱动的神经炎症中起重要作用。我们之前的研究表明，TREM2过表达对老年小鼠的神经炎症和认知缺陷具有保护作用。然而，TREM2在小胶质细胞中发挥作用的精确机制仍不清楚。因此，本研究旨在探讨TREM2在脂多糖（LPS）诱导的BV2细胞死亡和神经炎症中的作用。本研究通过蛋白质印迹分析、流式细胞术和酶联免疫吸附测定表明，TREM2可减少LPS诱导的核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）介导的细胞焦亡以及随后炎症因子的释放。最近的研究表明，小胶质细胞中TREM2的下游受体激酶脾酪氨酸激酶（SYK）缺失会导致神经炎症性疾病加重。本研究进一步证明，通过TREM2处理激活SYK可减轻LPS诱导的BV2细胞线粒体膜电位损伤，促进线粒体自噬，并抑制NLRP3介导的细胞焦亡，从而发挥神经保护作用。相反，R406抑制SYK会导致小胶质细胞死亡并加重神经炎症，从而降低TREM2的神经保护作用。我们的研究结果表明，TREM2和SYK可减轻LPS诱导的BV2小胶质细胞中的炎症反应，并通过增强线粒体自噬来干扰细胞焦亡。这些发现表明，TREM2和SYK可能是神经炎症的有价值治疗靶点。
