Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China; Department of Immunology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity at Bengbu Medical University, Bengbu, Anhui 233030, PR China; Department of Clinical Laboratory, Air Force Medical Center, Air Force Medical University, Beijing, 100142, PR China.
Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China.
Exp Neurol. 2024 Jul;377:114784. doi: 10.1016/j.expneurol.2024.114784. Epub 2024 Apr 19.
Inflammation is one of the key injury factors for spinal cord injury (SCI). Exosomes (Exos) derived from M2 macrophages have been shown to inhibit inflammation and be beneficial in SCI animal models. However, lacking targetability restricts their application prospects. Considering that chemokine receptors increase dramatically after SCI, viral macrophage inflammatory protein II (vMIP-II) is a broad-spectrum chemokine receptor binding peptide, and lysosomal associated membrane protein 2b (Lamp2b) is the key membrane component of Exos, we speculated that vMIP-II-Lamp2b gene-modified M2 macrophage-derived Exos (vMIP-II-Lamp2b-M2-Exo) not only have anti-inflammatory properties, but also can target the injured area by vMIP-II. In this study, using a murine contusive SCI model, we revealed that vMIP-II-Lamp2b-M2-Exo could target the chemokine receptors which highly expressed in the injured spinal cords, inhibit some key chemokine receptor signaling pathways (such as MAPK and Akt), further inhibit proinflammatory factors (such as IL-1β, IL-6, IL-17, IL-18, TNF-α, and iNOS), and promote anti-inflammatory factors (such as IL-4 and Arg1) productions, and the transformation of microglia/macrophages from M1 into M2. Moreover, the improved histological and functional recoveries were also found. Collectively, our results suggest that vMIP-II-Lamp2b-M2-Exo may provide neuroprotection by targeting the injured spinal cord, inhibiting some chemokine signals, reducing proinflammatory factor production and modulating microglia/macrophage polarization.
炎症是脊髓损伤 (SCI) 的关键损伤因素之一。已经证明，M2 巨噬细胞来源的外泌体 (Exos) 抑制炎症，并在 SCI 动物模型中有益。然而，缺乏靶向性限制了它们的应用前景。鉴于 SCI 后趋化因子受体急剧增加，病毒巨噬细胞炎症蛋白 II (vMIP-II) 是一种广谱趋化因子受体结合肽，溶酶体相关膜蛋白 2b (Lamp2b) 是 Exos 的关键膜成分，我们推测 vMIP-II-Lamp2b 基因修饰的 M2 巨噬细胞衍生的 Exos (vMIP-II-Lamp2b-M2-Exo) 不仅具有抗炎特性，而且可以通过 vMIP-II 靶向损伤区域。在这项研究中，我们使用了一种小鼠挫伤性 SCI 模型，揭示了 vMIP-II-Lamp2b-M2-Exo 可以靶向在损伤脊髓中高度表达的趋化因子受体，抑制一些关键的趋化因子受体信号通路（如 MAPK 和 Akt），进一步抑制促炎因子（如 IL-1β、IL-6、IL-17、IL-18、TNF-α 和 iNOS），并促进抗炎因子（如 IL-4 和 Arg1）的产生，以及小胶质细胞/巨噬细胞从 M1 向 M2 的转化。此外，还发现了组织学和功能的改善恢复。总之，我们的研究结果表明，vMIP-II-Lamp2b-M2-Exo 可能通过靶向损伤的脊髓、抑制某些趋化因子信号、减少促炎因子的产生和调节小胶质细胞/巨噬细胞极化来提供神经保护。
