Ma Chao, Wang Yansong
Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China; Heilongjiang Provincial Key Laboratory of Hard Tissue Development and Regeneration, Harbin Medical University, Harbin, China.
Brain Res Bull. 2025 Jan;220:111139. doi: 10.1016/j.brainresbull.2024.111139. Epub 2024 Nov 23.
Spinal cord injury (SCI) is a devastating disease characterized by neuroinflammation and irreversible neuronal loss. The basic helix-loop-helix family member e40 (Bhlhe40) is a stress-responsive transcription factor involved in the pathological process of inflammation. However, Bhlhe40 expression and its role in SCI are largely unknown. SCI rat models were established with an aneurysm clip and then the rats were injected with lentiviral Bhlhe40 shRNA to knock down Bhlhe40 expression. In vitro, BV2 microglia cells were stimulated with LPS and IFN-γ to promote M1 microglia polarization. The results showed that Bhlhe40 expression was significantly elevated in the injured spinal cord tissue. Bhlhe40 deficiency reduced neuroinflammation and neuronal loss, and then promoted the recovery of neurological function. Additionally, Bhlhe40 knockdown alleviated neuronal apoptosis by regulating microglia polarization. In our study, Bhlhe40 knockdown inhibited M1 microglia polarization and the secretion of pro-inflammatory factors (TNF-α, IL-1β, and IL-6). Meanwhile, the NF-κB pathway was inhibited after the Bhlhe40 knockdown in SCI rats. To further explore the functional role of Bhlhe40, we performed in vitro experiments. Bhlhe40 knockdown decreased M1 microglia polarization by inhibiting the NF-κB pathway. In conclusion, our study indicates that Bhlhe40 knockdown can alleviate the progression of SCI and its underlying mechanism in regulating macrophage polarization through the NF-κB pathway.
脊髓损伤（SCI）是一种以神经炎症和不可逆神经元丢失为特征的毁灭性疾病。碱性螺旋-环-螺旋家族成员e40（Bhlhe40）是一种参与炎症病理过程的应激反应转录因子。然而，Bhlhe40在脊髓损伤中的表达及其作用在很大程度上尚不清楚。用动脉瘤夹建立脊髓损伤大鼠模型，然后给大鼠注射慢病毒Bhlhe40 shRNA以敲低Bhlhe40表达。在体外，用脂多糖（LPS）和干扰素-γ刺激BV2小胶质细胞以促进M1小胶质细胞极化。结果显示，损伤脊髓组织中Bhlhe40表达显著升高。Bhlhe40缺乏减轻了神经炎症和神经元丢失，进而促进了神经功能的恢复。此外，敲低Bhlhe40通过调节小胶质细胞极化减轻了神经元凋亡。在我们的研究中，敲低Bhlhe40抑制了M1小胶质细胞极化和促炎因子（肿瘤坏死因子-α、白细胞介素-1β和白细胞介素-6）的分泌。同时，脊髓损伤大鼠敲低Bhlhe40后，核因子-κB（NF-κB）通路受到抑制。为了进一步探究Bhlhe40的功能作用，我们进行了体外实验。敲低Bhlhe40通过抑制NF-κB通路减少了M1小胶质细胞极化。总之，我们的研究表明，敲低Bhlhe40可减轻脊髓损伤的进展，其潜在机制是通过NF-κB通路调节巨噬细胞极化。
