Ma Xiaoxia, Mai Lijia, He Yifan, Jia Shilin, Yang Ruihan, Fan Wenguo, Huang Fang
Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China; Institute of Stomatological Research, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.
Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China; Institute of Stomatological Research, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.
Neuroscience. 2025 Aug 6;580:115-123. doi: 10.1016/j.neuroscience.2025.06.026. Epub 2025 Jun 13.
Chemokines are known to play a role in the nervous system, involving a wide range of functions including the development of chronic pain. The C-C motif chemokine ligand 12 (CCL12) and its receptor CCR2 have been implicated in the pathophysiology of chronic pian. However, the precise mechanisms by which CCL12 influences the development and persistence of pain remain unclear. In this study, we aim to investigate the roles of CCL12 in chronic inflammatory pain at the primary sensory ganglion level. A mouse model of orofacial pain was established by subcutaneous injection of complete Freud's adjuvant (CFA) into the right whisker pad. Mechanical allodynia was assessed using the von Frey test. The expression of CCL12 in the trigeminal ganglion (TG) was markedly upregulated at 7 days post-injection (dpi). Immunofluorescence and single-cell RNA-sequencing (scRNA-seq) data revealed that CCR2 was predominantly expressed in macrophages in the TG following CFA injection. To specifically target CCL12, an interfering adeno-associated virus (AAV) was administered intraganglionically into the right TG. Knockdown of Ccl12 in the TG significantly alleviated mechanical allodynia and c-Fos expression in the spinal trigeminal nucleus caudalis (SpVc) of CFA mice. Additionally, the infiltration of macrophages and the levels of IL-6 and TNF-α in the TG were significantly increased at 7 dpi and were attenuated by Ccl12 knockdown. These findings suggest that CCL12 contributes to CFA-induced orofacial allodynia by promoting macrophage infiltration and the production of IL-6 and TNF-α in the TG.
已知趋化因子在神经系统中发挥作用，涉及包括慢性疼痛发展在内的广泛功能。C-C基序趋化因子配体12（CCL12）及其受体CCR2与慢性疼痛的病理生理学有关。然而，CCL12影响疼痛发展和持续的精确机制仍不清楚。在本研究中，我们旨在研究CCL12在初级感觉神经节水平的慢性炎症性疼痛中的作用。通过将完全弗氏佐剂（CFA）皮下注射到右侧须垫建立口面部疼痛小鼠模型。使用von Frey试验评估机械性异常性疼痛。注射后7天（dpi）三叉神经节（TG）中CCL12的表达明显上调。免疫荧光和单细胞RNA测序（scRNA-seq）数据显示，CFA注射后TG中的巨噬细胞中主要表达CCR2。为了特异性靶向CCL12，将干扰腺相关病毒（AAV）神经节内注射到右侧TG中。TG中Ccl12的敲低显著减轻了CFA小鼠脊髓三叉神经尾核（SpVc）中的机械性异常性疼痛和c-Fos表达。此外，TG中巨噬细胞的浸润以及IL-6和TNF-α的水平在7 dpi时显著增加，并通过Ccl12敲低而减弱。这些发现表明，CCL12通过促进巨噬细胞浸润以及TG中IL-6和TNF-α的产生，导致CFA诱导的口面部异常性疼痛。
