Ji Yan-Zhe, Lin Zhi-Hao, Liao Cai-Xian, Wang Qian, Chen Fang-Yu, Su Wen-Feng, Zhao Ya-Yu, Chen Gang, Wei Zhong-Ya
Co-Innovation Center of Neuroregeneration, Medical School of Nantong University, Nantong, 226001, Jiangsu, China.
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
Inflammation. 2025 Apr 25. doi: 10.1007/s10753-025-02300-w.
Neuropathic pain is characterized by a high prevalence and associated with a variety of disorders of the peripheral and central nervous systems. It remains a major challenge for clinical management due to lack effective treatments. Our previous studies have demonstrated that nerve injury-induced neuroinflammation plays a critical role in regulating the development and maintenance of neuropathic pain. In the present study, we found that chronic constriction injury (CCI) led to a significant increase in the number of macrophages at the site of injured nerves. To elucidate the role of macrophage activation in CCI-induced neuropathic pain, we employed chemical agents, including clodronate liposomes, which is known for their ability to deplete macrophages, and minocycline, an inhibitor of macrophage function. Both intravenous injection of liposome-encapsulated clodronate and intrasciatic delivery of minocycline effectively attenuated CCI-induced mechanical and heat hyperalgesia. Furthermore, transfer of polarized M2 macrophages significantly alleviated CCI-induced neuropathic pain, but not under the condition of M1 macrophage transfer. Mechanistically, our findings indicated that pretreatment with minocycline increased the expression level of CD206 but decreased that of IL-1β, while post-polarization treatment markedly decreased the expression level of both. Additionally, an in vitro migration assay revealed that minocycline exerts an inhibitory effect on macrophage migration. In brief, our study elucidates the effect of CCI-induced macrophage activation on neuropathic pain and provides new insights into the potential clinical application of minocycline for managing neuropathic pain.
神经病理性疼痛具有高发病率的特点，并与多种外周和中枢神经系统疾病相关。由于缺乏有效的治疗方法，它仍然是临床治疗的一大挑战。我们之前的研究表明，神经损伤诱导的神经炎症在调节神经病理性疼痛的发生和维持中起关键作用。在本研究中，我们发现慢性缩窄损伤（CCI）导致受损神经部位的巨噬细胞数量显著增加。为了阐明巨噬细胞活化在CCI诱导的神经病理性疼痛中的作用，我们使用了化学试剂，包括以能够消耗巨噬细胞而闻名的氯膦酸脂质体和巨噬细胞功能抑制剂米诺环素。静脉注射脂质体包裹的氯膦酸和坐骨神经内注射米诺环素均有效减轻了CCI诱导的机械性和热痛觉过敏。此外，极化的M2巨噬细胞的转移显著减轻了CCI诱导的神经病理性疼痛，但在M1巨噬细胞转移的情况下则没有。从机制上讲，我们的研究结果表明，米诺环素预处理增加了CD206的表达水平，但降低了IL-1β的表达水平，而极化后处理则显著降低了两者的表达水平。此外，体外迁移试验表明米诺环素对巨噬细胞迁移具有抑制作用。简而言之，我们的研究阐明了CCI诱导的巨噬细胞活化对神经病理性疼痛的影响，并为米诺环素在治疗神经病理性疼痛方面的潜在临床应用提供了新见解。
