Department of Orthopaedic Surgery, Orthopaedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China.
Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.
J Nanobiotechnology. 2024 May 31;22(1):301. doi: 10.1186/s12951-024-02556-8.
Intervertebral disc degeneration (IVDD) is the primary factor contributing to low back pain (LBP). Unlike elderly patients, many young IVDD patients usually have a history of trauma or long-term abnormal stress, which may lead to local inflammatory reaction causing by immune cells, and ultimately accelerates degeneration. Research has shown the significance of M1-type macrophages in IVDD; nevertheless, the precise mechanism and the route by which it influences the function of nucleus pulposus cell (NPC) remain unknown. Utilizing a rat acupuncture IVDD model and an NPC degeneration model induced by lipopolysaccharide (LPS), we investigated the function of M1 macrophage-derived exosomes (M1-Exos) in IVDD both in vivo and in vitro in this study. We found that M1-Exos enhanced LPS-induced NPC senescence, increased the number of SA-β-gal-positive cells, blocked the cell cycle, and promoted the activation of P21 and P53. M1-Exos derived from supernatant pretreated with the exosome inhibitor GW4869 reversed this result in vivo and in vitro. RNA-seq showed that Lipocalin2 (LCN2) was enriched in M1-Exos and targeted the NF-κB pathway. The quantity of SA-β-gal-positive cells was significantly reduced with the inhibition of LCN2, and the expression of P21 and P53 in NPCs was decreased. The same results were obtained in the acupuncture-induced IVDD model. In addition, inhibition of LCN2 promotes the expression of type II collagen (Col-2) and inhibits the expression of matrix metalloproteinase 13 (MMP13), thereby restoring the equilibrium of metabolism inside the extracellular matrix (ECM) in vitro and in vivo. In addition, the NF-κB pathway is crucial for regulating M1-Exo-mediated NPC senescence. After the addition of M1-Exos to LPS-treated NPCs, p-p65 activity was significantly activated, while si-LCN2 treatment significantly inhibited p-p65 activity. Therefore, this paper demonstrates that M1 macrophage-derived exosomes have the ability to deliver LCN2, which activates the NF-κB signaling pathway, and exacerbates IVDD by accelerating NPC senescence. This may shed new light on the mechanism of IVDD and bring a fresh approach to IVDD therapy.
椎间盘退行性病变（IVDD）是导致下腰痛（LBP）的主要因素。与老年患者不同，许多年轻的 IVDD 患者通常有创伤或长期异常应激的病史，这可能导致免疫细胞引起的局部炎症反应，并最终加速退行性变。研究表明，M1 型巨噬细胞在 IVDD 中具有重要意义；然而，其影响髓核细胞（NPC）功能的确切机制和途径尚不清楚。在这项研究中，我们利用大鼠针刺 IVDD 模型和脂多糖（LPS）诱导的 NPC 退变模型，在体内和体外研究了 M1 巨噬细胞衍生的外泌体（M1-Exos）在 IVDD 中的作用。我们发现，M1-Exos 增强了 LPS 诱导的 NPC 衰老，增加了 SA-β-gal 阳性细胞的数量，阻断了细胞周期，并促进了 P21 和 P53 的激活。体内和体外实验均证实，用外泌体抑制剂 GW4869预处理上清液得到的 M1-Exos 可逆转这一结果。RNA-seq 显示，脂钙蛋白 2（LCN2）在 M1-Exos 中富集，并靶向 NF-κB 通路。抑制 LCN2 后，SA-β-gal 阳性细胞数量明显减少，NPC 中 P21 和 P53 的表达减少。针刺诱导的 IVDD 模型也得到了相同的结果。此外，抑制 LCN2 可促进 II 型胶原（Col-2）的表达，并抑制基质金属蛋白酶 13（MMP13）的表达，从而在体外和体内恢复细胞外基质（ECM）代谢平衡。此外，NF-κB 通路对调节 M1-Exo 介导的 NPC 衰老至关重要。在 LPS 处理的 NPC 中加入 M1-Exos 后，p-p65 活性明显被激活，而 si-LCN2 处理则显著抑制 p-p65 活性。因此，本文表明，M1 巨噬细胞衍生的外泌体具有传递 LCN2 的能力，激活 NF-κB 信号通路，并通过加速 NPC 衰老加重 IVDD。这可能为 IVDD 的发病机制提供新的见解，并为 IVDD 的治疗带来新的方法。
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