CXCL13 contributes to chronic pain of a mouse model of CRPS-I via CXCR5-mediated NF-κB activation and pro-inflammatory cytokine production in spinal cord dorsal horn

作者：Jie Wang, Chengyu Yin, Yushuang Pan, Yunqin Yang, Wei Li, Huadong Ni, Boyu Liu, Boyu Liu, Huimin Nie, Ruoyao Xu, Huina Wei, Yunwen Zhang, Yuanyuan Li, Qimiao Hu, Yan Tai, Xiaomei Shao, Jianqiao Fang, Boyi Liu, Boyi Liu · 发表于：Journal of Neuroinflammation · 年份：2023 · DOI：10.1186/s12974-023-02778-x · 被引用次数：42 · 研究领域：Pain Management and Treatment、Pain Mechanisms and Treatments、Spine and Intervertebral Disc Pathology

Abstract Background Complex regional pain syndrome type-I (CRPS-I) causes excruciating pain that affect patients’ life quality. However, the mechanisms underlying CRPS-I are incompletely understood, which hampers the development of target specific therapeutics. Methods The mouse chronic post-ischemic pain (CPIP) model was established to mimic CRPS-I. qPCR, Western blot, immunostaining, behavioral assay and pharmacological methods were used to study mechanisms underlying neuroinflammation and chronic pain in spinal cord dorsal horn (SCDH) of CPIP mice. Results CPIP mice developed robust and long-lasting mechanical allodynia in bilateral hindpaws. The expression of inflammatory chemokine CXCL13 and its receptor CXCR5 was significantly upregulated in ipsilateral SCDH of CPIP mice. Immunostaining revealed CXCL13 and CXCR5 was predominantly expressed in spinal neurons. Neutralization of spinal CXCL13 or genetic deletion of Cxcr5 ( Cxcr5 −/− ) significantly reduced mechanical allodynia, as well as spinal glial cell overactivation and c-Fos activation in SCDH of CPIP mice. Mechanical pain causes affective disorder in CPIP mice, which was attenuated in Cxcr5 −/− mice. Phosphorylated STAT3 co-expressed with CXCL13 in SCDH neurons and contributed to CXCL13 upregulation and mechanical allodynia in CPIP mice. CXCR5 coupled with NF-κB signaling in SCDH neurons to trigger pro-inflammatory cytokine gene Il6 upregulation, contributing to mechanical allodynia. Intrathecal CXCL13 injection pro...