Neuron-derived CCL3 drives neuropathic pain after brachial plexus avulsion in mice

A chemokine produced by neurons in the spinal cord appears to play a central role in the severe neuropathic pain that follows brachial plexus avulsion, a traumatic injury in which nerve roots are torn from the spinal cord, according to a new mouse study published in Cell & Bioscience. The research identifies C–C motif chemokine ligand 3, or CCL3, as a key mediator of pain and central sensitization in the spinal dorsal horn, the region of the spinal cord that receives and processes sensory signals.

Brachial plexus avulsion inflicts direct damage on the dorsal horn of the spinal cord, yet the mechanisms that convert this injury into chronic neuropathic pain have remained poorly understood. The research team set out to determine what role, if any, CCL3 and its receptor CCR1 play in the ipsilateral spinal dorsal horn during the development of this pain state.

To investigate, the researchers established a novel mouse model of brachial plexus avulsion and assessed pain behavior using von Frey filament tests, a cold plate test and CatWalk gait analysis. They then used RNA sequencing to detect differentially expressed genes in the ipsilateral cervical spinal dorsal horn after the injury, and evaluated CCL3 and CCR1 expression through Western blotting and immunohistochemistry.

The analysis revealed that CCL3 was highly expressed in the ipsilateral spinal dorsal horn of injured mice, a finding confirmed by Western blot. Notably, the chemokine was found predominantly in activated neurons, marked by both c-fosTdTomato and CaMKII positivity, rather than in other cell types. When the researchers chemogenetically inhibited these neurons, the pain of the injured mice was relieved.

The team also tested whether blocking CCL3 signaling could ease the pain. Both a pharmacological antagonist of the receptor CCR1 and genetic knockdown of CCL3 in neurons relieved pain in the injured mice, indicating that the neuron-derived chemokine and its receptor form a functionally relevant signaling pair in this pain model.

Transcriptomic data pointed to a possible upstream pathway, TLR2-IRF5-CCL3, and the researchers report that their results support the potential involvement of this axis in the analgesic response, consistent with a regulatory contribution of the pathway as assessed by Western blot and pharmacological methods. The authors describe this as a possible signaling pathway supported by their experimental observations rather than a fully established mechanism.

Beyond the chemokine axis, the study documented gliosis, the activation of glial cells, occurring as a consequence of the direct injury to the spinal dorsal horn, as visualized by immunohistochemistry. Importantly, this glial activation could be mitigated by treatment with the CCR1 antagonist, linking receptor signaling to the neuroinflammatory response that follows the injury.

The findings add to evidence that neuroinflammation and glial cell activation help drive central sensitization, the amplification of pain signaling within the central nervous system, under chronic pain conditions, particularly after brachial plexus avulsion.

The study was conducted in a mouse model, and the authors note that the work supports the involvement of CCL3 in modulating brachial plexus avulsion-induced neuropathic pain via the potential TLR2-IRF5-CCL3 signaling pathway during spinal central sensitization. As with all preclinical research, further work will be needed to determine whether these mechanisms and any therapeutic targeting of CCR1 or CCL3 would apply to human patients with this devastating injury.

The article, published open access on 30 September 2026, was authored by Lu Yang, Huan Guo, Hang Zhang, Shi-Hao Peng, Jie Ren, Rui Cong and Hang Xian. The publisher notes that the shared version is an accepted manuscript released early for faster access, subject to further edits before the final version of record.

Subject of Research: The role of neuron-derived chemokine CCL3 in spinal dorsal horn-mediated neuropathic pain after brachial plexus avulsion in mice.

Article Title: Neuron-derived chemokine CCL3 in spinal dorsal horn mediates brachial plexus avulsion-induced neuropathic pain and related central sensitization

Article References: Yang, L., Guo, H., Zhang, H., Peng, S.-H., Ren, J., Cong, R., & Xian, H. (2026). Neuron-derived chemokine CCL3 in spinal dorsal horn mediates brachial plexus avulsion-induced neuropathic pain and related central sensitization. Cell & Bioscience. https://doi.org/10.1186/s13578-026-01657-1

Image Credits: AI Generated

DOI: 10.1186/s13578-026-01657-1

Keywords: CCL3, CCR1, brachial plexus avulsion, neuropathic pain, central sensitization, spinal dorsal horn, neuroinflammation, gliosis, TLR2-IRF5-CCL3 signaling, mouse model, chemokine, Neuron-derived