Zhang Haocong, Xiang Liangbi, Yuan Hong, Yu Hailong
Department of Orthopaedics, The General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang, Liaoning, China.
Department of Orthopaedics, The General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang, Liaoning, China.
Biochim Biophys Acta Mol Cell Res. 2025 Feb;1872(2):119882. doi: 10.1016/j.bbamcr.2024.119882. Epub 2024 Nov 26.
Neuroinflammation-caused secondary injury is a key event after spinal cord injury (SCI). Dedicator of cytokinesis 2 (DOCK2) belonging to DOCK-A subfamily has a vital role in microglia polarization and neuroinflammation via mediating Rac activation. However, the role of DOCK2 in SCI is unclear. In the present study, SCI model in mice was established by an impactor at thoracic T10 level. DOCK2 expression was significantly increased in the spinal cord after SCI. After knocking down DOCK2 using a lentivirus-mediated method, SCI mice exhibited improved motor function recovery, as revealed by increased Basso Mouse Scale (BMS) score, angle of incline, and relatively coordinated footprint, and decreased damaged area in the spinal cord. DOCK2 deficiency reduced neuronal apoptosis in the spinal cord after injury. Besides, deficiency of DOCK2 suppressed neuroinflammation after SCI, demonstrated by the reduction in pro-inflammatory mediators including IFN-γ, IL-1β and IL-6 and the increase in IL-4, IL-10 and IL-13, anti-inflammatory factors. The CD86, iNOS and COX-2 were down-regulated in the spinal cord, whereas CD206, Arg-1 and TGF-β were up-regulated by DOCK2 deficiency. Rac activation was prevented by DOCK2 deficiency following SCI. In vitro experiments were conducted for further verification. Treatment of BV-2 microglia with lentivirus-mediated DOCK2 inhibited IFN-γ/LPS-induced pro-inflammatory microglia polarization but increased IL-4-induced anti-inflammatory microglia, through inhibiting Rac activation. In brief, our data reveal that DOCK2 deficiency improves functional recovery in mice after SCI, which is related to Rac activation.
神经炎症引起的继发性损伤是脊髓损伤（SCI）后的关键事件。属于DOCK - A亚家族的细胞分裂素2（DOCK2）通过介导Rac激活在小胶质细胞极化和神经炎症中起重要作用。然而，DOCK2在脊髓损伤中的作用尚不清楚。在本研究中，通过在胸段T10水平使用撞击器建立小鼠脊髓损伤模型。脊髓损伤后脊髓中DOCK2表达显著增加。使用慢病毒介导的方法敲低DOCK2后，脊髓损伤小鼠的运动功能恢复得到改善，表现为巴索小鼠量表（BMS）评分增加、倾斜角度增加和足迹相对协调，并且脊髓损伤面积减小。DOCK2缺乏减少了损伤后脊髓中的神经元凋亡。此外，DOCK2缺乏抑制了脊髓损伤后的神经炎症，表现为促炎介质如IFN - γ、IL - 1β和IL - 6减少，以及抗炎因子IL - 4、IL - 10和IL - 13增加。脊髓损伤后，DOCK2缺乏使CD86、诱导型一氧化氮合酶（iNOS）和环氧化酶 - 2（COX - 2）下调，而使CD206、精氨酸酶 - 1（Arg - 1）和转化生长因子 - β（TGF - β）上调。脊髓损伤后DOCK2缺乏阻止了Rac激活。进行体外实验进一步验证。用慢病毒介导的DOCK2处理BV - 2小胶质细胞可抑制IFN - γ/脂多糖（LPS）诱导的促炎性小胶质细胞极化，但通过抑制Rac激活增加IL - 4诱导的抗炎性小胶质细胞。简而言之，我们的数据表明DOCK2缺乏可改善小鼠脊髓损伤后的功能恢复，这与Rac激活有关。
