Department of Orthopaedics, The General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang, Liaoning, 110016, China.
Department of Orthopaedics, The General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang, Liaoning, 110016, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Jun;1870(5):167141. doi: 10.1016/j.bbadis.2024.167141. Epub 2024 Mar 31.
Spinal cord injury (SCI) induces severe neuroinflammation, and subsequently neurological dysfunction. Activated microglia are critical for modulation of neuroinflammation. Protein tyrosine phosphatase receptor type O (PTPRO), a member of protein tyrosine phosphatases (PTPs), exerts a pro-inflammatory role in multiple human diseases; however, its role in SCI remains unclarified. Here, a T7 spinal cord compression injury model was established in Sprague-Dawley (SD) rats, and PTPRO expression was upregulated in injured spinal cord and microglia after SCI. Microglia M1 and M2 polarization in vitro were induced using LPS/IFN-γ and IL-4, respectively. PTPRO expression was elevated in M1-polarized microglia, and PTPRO downregulation mediated by PTPRO shRNA (shPTPRO) decreased CD86 cell proportion, iNOS, TNF-α, IL-1β, and IL-6 levels, and p65 phosphorylation. PTPRO was downregulated in M2 microglia, and PTPRO upregulation by PTPRO overexpression plasmid (OE-PTPRO) reduced CD206 cell percentage, Arg-1, IL-10, and TGF-β1 levels and STAT6 phosphorylation. Mechanistically, the transcription factor SOX4 elevated PTPRO expression and its promoter activity. SOX4 overexpression enhanced M1 polarization and p65 phosphorylation, while its knockdown promoted M2 polarization and STAT6 phosphorylation. PTPRO might mediate the function of SOX4 in BV2 microglia polarization. Furthermore, lentivirus-mediated downregulation of PTPRO following SCI improved locomotor functional recovery, demonstrated by elevated BBB scores, incline angle, consistent hindlimb coordination, and reduced lesion area and neuronal apoptosis. PTPRO downregulation promoted microglia M2 polarization, NF-κB inactivation and STAT6 activation after injury. In conclusion, PTPRO inhibition improves spinal cord injury through facilitating M2 microglia polarization via the NF-κB/STAT6 signaling pathway, which is probably controlled by SOX4.
脊髓损伤 (SCI) 会引起严重的神经炎症，进而导致神经功能障碍。激活的小胶质细胞对神经炎症的调节至关重要。蛋白酪氨酸磷酸酶受体 O 型 (PTPRO) 是蛋白酪氨酸磷酸酶 (PTPs) 的成员之一，在多种人类疾病中发挥促炎作用；然而，其在 SCI 中的作用尚不清楚。在这里，我们在 Sprague-Dawley (SD) 大鼠中建立了 T7 脊髓压迫损伤模型，发现 SCI 后损伤脊髓和小胶质细胞中 PTPRO 表达上调。使用 LPS/IFN-γ 和 IL-4 分别诱导体外小胶质细胞 M1 和 M2 极化。M1 极化的小胶质细胞中 PTPRO 表达上调，而 PTPRO shRNA (shPTPRO) 下调 PTPRO 表达可降低 CD86 细胞比例、iNOS、TNF-α、IL-1β 和 IL-6 水平及 p65 磷酸化。M2 小胶质细胞中 PTPRO 表达下调，而过表达 PTPRO 质粒 (OE-PTPRO) 下调 PTPRO 表达可降低 CD206 细胞比例、Arg-1、IL-10 和 TGF-β1 水平及 STAT6 磷酸化。机制上，转录因子 SOX4 上调 PTPRO 表达及其启动子活性。SOX4 过表达增强了 M1 极化和 p65 磷酸化，而敲低则促进了 M2 极化和 STAT6 磷酸化。PTPRO 可能介导 SOX4 在 BV2 小胶质细胞极化中的功能。此外，SCI 后小胶质细胞中 PTPRO 的慢病毒介导下调通过促进 M2 小胶质细胞极化来改善运动功能恢复，表现为 BBB 评分升高、倾斜角度增加、后肢协调一致、损伤面积减小和神经元凋亡减少。PTPRO 下调促进了损伤后小胶质细胞 M2 极化、NF-κB 失活和 STAT6 激活。总之，通过促进 M2 小胶质细胞极化，PTPRO 抑制改善了脊髓损伤，NF-κB/STAT6 信号通路可能由 SOX4 控制。
