Center for Clinical Laboratories, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China; Department of Clinical Laboratory, Guizhou Hospital, the First Affiliated Hospital of Sun Yat-sen University, Guiyang 550004, China.
Clinical Research Center, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China.
Int Immunopharmacol. 2024 Dec 5;142(Pt A):112849. doi: 10.1016/j.intimp.2024.112849. Epub 2024 Sep 5.
Multiple sclerosis (MS) is a neurodegenerating autoimmune disease with no clinical cure currently. The calcium-binding protein S100A4 has been demonstrated to exert regulatory roles in inflammatory disorders including MS. However, the precise mechanisms by which S100A4 regulates neuroinflammation in MS remains unknown. To investigate the regulatory effect of S100A4 on microglial inflammation and its impact on neuroinflammation, the mouse-derived microglia cell line BV2 cells were infected with lentivirus to knockout S100A4 for in vitro studies. Wild-type (WT) and S100A4 mice were induced to develop experimental autoimmune encephalomyelitis (EAE), an animal model of MS, for in vivo investigation. Results indicated that the frequencies of microglia in the spinal cord and brain and the expression of S100A4 in these tissues varied kinetically along with the progression of the disease in mice with EAE. S100A4 mice presented ameliorated clinical scores of EAE and exhibited less severe EAE signs, including inflammatory cell infiltration in the spinal cord and brain and demyelination of the spinal cord. Moreover, these mice demonstrated overall reduced levels of inflammatory cytokines in the spinal cord and brain. Compromised systematic inflammatory responses including circulating cytokines and frequencies of immune cells in the spleen were also observed in these mice. In addition, both exogenous and endogenous S100A4 could promote the microglial inflammation, affect the polarization of microglia and enhance inflamed microglia-mediated apoptosis of neuronal cells through TLR4/NF-κB signaling pathway. Thus, S100A4 may participate in the regulation of neuroinflammation at least partly through regulating the inflammation of microglia.
多发性硬化症（MS）是一种神经退行性自身免疫性疾病，目前尚无临床治愈方法。钙结合蛋白 S100A4 已被证明在包括 MS 在内的炎症性疾病中发挥调节作用。然而，S100A4 调节 MS 中神经炎症的确切机制尚不清楚。为了研究 S100A4 对小胶质细胞炎症的调节作用及其对神经炎症的影响，我们使用慢病毒感染小鼠源性小胶质细胞系 BV2 细胞以敲除 S100A4 进行体外研究。使用野生型（WT）和 S100A4 小鼠诱导实验性自身免疫性脑脊髓炎（EAE），即 MS 的动物模型，进行体内研究。结果表明，EAE 小鼠脊髓和脑组织中小胶质细胞的频率以及这些组织中 S100A4 的表达随疾病的进展呈动态变化。S100A4 小鼠的 EAE 临床评分得到改善，表现出更轻微的 EAE 症状，包括脊髓和脑组织中的炎症细胞浸润和脱髓鞘。此外，这些小鼠脊髓和脑组织中的炎症细胞因子水平总体降低。这些小鼠还表现出循环细胞因子和脾脏免疫细胞频率等全身性炎症反应受损。此外，外源性和内源性 S100A4 均可通过 TLR4/NF-κB 信号通路促进小胶质细胞炎症，影响小胶质细胞的极化，并增强炎症小胶质细胞介导的神经元细胞凋亡。因此，S100A4 可能通过调节小胶质细胞炎症至少部分参与神经炎症的调节。
