Sun Shujun, Sun Yan, Shen Jiwei, Mao Zhangyan, Zhang Tianhao, Gao Yafen, Yang Dong, Chen Xiangdong, Song Guobin
Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Int J Surg. 2025 Jun 20. doi: 10.1097/JS9.0000000000002764.
Pain is a significant global health burden, and current treatments often fail to provide adequate relief due to an incomplete understanding of its mechanisms. This review integrates emerging evidence highlighting the CXCL13/CXCR5 chemokine pathway as a crucial mediator across various pain states, including nociceptive, inflammatory, and neuropathic pain. CXCL13 and CXCR5 are substantially upregulated in pain-related regions such as the spinal cord, dorsal root ganglia (DRG), and cerebrospinal fluid following nerve injury, inflammation, and in conditions like bone cancer or diabetes. The key mechanisms through which they contribute to pain include enhancing neuronal excitability by increasing Nav1.8 sodium channel currents in DRG neurons via p38 MAPK signaling, promoting neuroinflammation by activating NF-κB, ERK, and JNK pathways, which drive the production of pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-1β) and immune cell infiltration, and activating glial cells, where CXCL13/CXCR5 signaling promotes astrocyte reactivity and indirectly activates microglia, thereby amplifying central sensitization. Genetic knockdown or pharmacological inhibition of CXCL13/CXCR5 has been shown to significantly reduce pain hypersensitivity in preclinical models. The pathway's high tissue specificity in pain pathways and its multifaceted regulation of pain mechanisms make it a promising novel therapeutic target. Future research should address CXCL13/CXCR5 interactions with other pain-related pathways (e.g., CXCL12/CXCR4), explore non-GPCR signaling (e.g., β-arrestins), and validate its potential as a clinical biomarker to guide targeted analgesic development.
疼痛是一项重大的全球健康负担，由于对其机制的理解不完整，目前的治疗方法往往无法提供充分的缓解。本综述整合了新出现的证据，突出了CXCL13/CXCR5趋化因子途径作为各种疼痛状态（包括伤害性疼痛、炎症性疼痛和神经性疼痛）的关键介质。在神经损伤、炎症后以及在骨癌或糖尿病等情况下，CXCL13和CXCR5在脊髓、背根神经节（DRG）和脑脊液等疼痛相关区域大量上调。它们导致疼痛的关键机制包括通过p38丝裂原活化蛋白激酶信号通路增加DRG神经元中的Nav1.8钠通道电流来增强神经元兴奋性，通过激活NF-κB、ERK和JNK途径促进神经炎症，这些途径驱动促炎细胞因子（如TNF-α、IL-6、IL-1β）的产生和免疫细胞浸润，以及激活神经胶质细胞，其中CXCL13/CXCR5信号促进星形胶质细胞反应并间接激活小胶质细胞，从而放大中枢敏化。在临床前模型中，CXCL13/CXCR5的基因敲低或药物抑制已显示能显著降低疼痛超敏反应。该途径在疼痛通路中的高组织特异性及其对疼痛机制的多方面调节使其成为一个有前景的新型治疗靶点。未来的研究应关注CXCL13/CXCR5与其他疼痛相关途径（如CXCL12/CXCR4）的相互作用，探索非GPCR信号（如β-抑制蛋白），并验证其作为临床生物标志物以指导靶向镇痛药物开发的潜力。
