2. Academic Validation
  3. SOX11-mediated CBLN2 Upregulation Contributes to Neuropathic Pain through NF-κB-Driven Neuroinflammation in Dorsal Root Ganglia of Mice

SOX11-mediated CBLN2 Upregulation Contributes to Neuropathic Pain through NF-κB-Driven Neuroinflammation in Dorsal Root Ganglia of Mice

  • Neurosci Bull. 2025 Oct 29. doi: 10.1007/s12264-025-01530-0.
Ling-Jie Ma # 1,  Tian Wang # 2,  Ting Xie # 2,  Lin-Peng Zhu 2,  Zuo-Hao Yao 2,  Meng-Na Li 2,  Bao-Tong Yuan 2,  Xiao-Bo Wu 2,  Yong-Jing Gao 3,  Yi-Bin Qin 4
Affiliations

Affiliations

  • 1 Department of Pain Management, Affiliated Hospital of Nantong University, Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Jiangsu, 226001, China. malingjie@ntu.edu.cn.
  • 2 Department of Pain Management, Affiliated Hospital of Nantong University, Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Jiangsu, 226001, China.
  • 3 Department of Pain Management, Affiliated Hospital of Nantong University, Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Jiangsu, 226001, China. gaoyongjing@ntu.edu.cn.
  • 4 Department of Pain Management, Affiliated Hospital of Nantong University, Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Jiangsu, 226001, China. jsntqyb@gmail.com.
  • # Contributed equally.
PMID: 41162740 DOI: 10.1007/s12264-025-01530-0
Abstract

Neuropathic pain, a debilitating condition caused by dysfunction of the somatosensory nervous system, remains difficult to treat due to limited understanding of its molecular mechanisms. Bioinformatics analysis identified cerebellin 2 (CBLN2) as highly enriched in human and murine proprioceptive and nociceptive neurons. We found that CBLN2 expression is persistently upregulated in dorsal root ganglia (DRG) following spinal nerve ligation (SNL) in mice. In addition, transcription factor SOX11 binds to 12 cis-regulatory elements within the Cbln2 promoter to enhance its transcription. SNL also induced SOX11 upregulation, with SOX11 and CBLN2 co-localized in nociceptive neurons. The siRNA-mediated knockdown of Sox11 or Cbln2 attenuated SNL-induced mechanical allodynia and thermal hyperalgesia. High-throughput Sequencing of DRG following intrathecal injection of CBLN2 revealed widespread gene expression changes, including upregulation of numerous NF-κB downstream targets. Consistently, CBLN2 activated NF-κB signaling, and inhibition with pyrrolidine dithiocarbamate reduced CBLN2-induced pain hypersensitivity, proinflammatory cytokines and chemokines production, and neuronal hyperexcitability. Together, these findings identified the SOX11/CBLN2/NF-κB axis as a critical mediator of neuropathic pain and a promising target for therapeutic intervention.

Keywords

CBLN2; Chemokines; NF-κB; Neuropathic pain; SOX11.

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