Orthopaedics/Department of Spine Surgery, Department of Pharmacy and Department of Gastroenterology, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China; State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
Orthopaedics/Department of Spine Surgery, Department of Pharmacy and Department of Gastroenterology, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China.
Int Immunopharmacol. 2024 Jun 15;134:112188. doi: 10.1016/j.intimp.2024.112188. Epub 2024 May 10.
Neuroinflammation is one of the extensive secondary injury processes that aggravate metabolic and cellular dysfunction and tissue loss following spinal cord injury (SCI). Thus, an anti-inflammatory strategy is crucial for modulating structural and functional restoration during the stage of acute and chronic SCI. Recombinant fibroblast growth factor 4 (rFGF4) has eliminated its mitogenic activity and demonstrated a metabolic regulator for alleviating hyperglycemia in type 2 diabetes and liver injury in non-alcoholic steatohepatitis. However, it remains to be explored whether or not rFGF4 has a neuroprotective effect for restoring neurological disorders, such as SCI. Here, we identified that rFGF4 could polarize microglia/macrophages into the restorative M2 subtype, thus exerting an anti-inflammatory effect to promote neurological functional recovery and nerve fiber regeneration after SCI. Importantly, these effects by rFGF4 were related to triggering PI3K/AKT/GSK3β and attenuating TLR4/NF-κB signaling axes. Conversely, gene silencing of the PI3K/AKT/GSK3β signaling or pharmacological reactivation of the TLR4/NF-κB axis aggravated inflammatory reaction. Thus, our findings highlight rFGF4 as a potentially therapeutic regulator for repairing SCI, and its outstanding effect is associated with regulating macrophage/microglial polarization.
神经炎症是脊髓损伤 (SCI) 后加重代谢和细胞功能障碍以及组织损失的广泛继发性损伤过程之一。因此，在急性和慢性 SCI 阶段，抗炎策略对于调节结构和功能恢复至关重要。重组成纤维细胞生长因子 4 (rFGF4) 消除了其有丝分裂活性，并表现出代谢调节剂的作用，可缓解 2 型糖尿病的高血糖和非酒精性脂肪性肝炎的肝损伤。然而，rFGF4 是否对恢复神经紊乱（如 SCI）具有神经保护作用仍有待探讨。在这里，我们发现 rFGF4 可以将小胶质细胞/巨噬细胞极化为修复性 M2 亚型，从而发挥抗炎作用，促进 SCI 后的神经功能恢复和神经纤维再生。重要的是，rFGF4 的这些作用与触发 PI3K/AKT/GSK3β 和减弱 TLR4/NF-κB 信号轴有关。相反，PI3K/AKT/GSK3β 信号的基因沉默或 TLR4/NF-κB 轴的药理学再激活加剧了炎症反应。因此，我们的研究结果强调了 rFGF4 作为修复 SCI 的潜在治疗调节剂，其突出的作用与调节巨噬细胞/小胶质细胞极化有关。
