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The CSF1-CSF1R pathway in the trigeminal ganglion mediates trigeminal neuralgia via inflammatory responses in mice

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Abstract

Background

Trigeminal neuralgia (TN) is the most severe type of neuropathic pain. The trigeminal ganglion (TG) is a crucial target for the pathogenesis and treatment of TN. The colony-stimulating factor 1 (CSF1) - colony-stimulating factor 1 receptor (CSF1R) pathway regulates lower limb pain development. However, the effect and mechanism of the CSF1-CSF1R pathway in TG on TN are unclear.

Methods

Partial transection of the infraorbital nerve (pT-ION) model was used to generate a mouse TN model. Mechanical and cold allodynia were used to measure pain behaviors. Pro-inflammatory factors (IL-6, TNF-a) were used to measure inflammatory responses in TG. PLX3397, an inhibitor of CSF1R, was applied to inhibit the CSF1-CSF1R pathway in TG. This pathway was activated in naïve mice by stereotactic injection of CSF1 into the TG.

Results

The TN model activated the CSF1-CSF1R pathway in the TG, leading to exacerbated mechanical and cold allodynia. TN activated inflammatory responses in the TG manifested as a significant increase in IL-6 and TNF-a levels. After using PLX3397 to inhibit CSF1R, CSF1R expression in the TG declined significantly. Inhibiting the CSF1-CSF1R pathway in the TG downregulated the expression of IL-6 and TNF-α to reduce allodynia-related behaviors. Finally, mechanical allodynia behaviors were exacerbated in naïve mice after activating the CSF1-CSF1R pathway in the TG.

Conclusions

The CSF1-CSF1R pathway in the TG modulates TN by regulating neuroimmune responses. Our findings provide a theoretical basis for the development of treatments for TN in the TG.

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Data availability

The datasets used in this study are available from the corresponding author upon reasonable request.

References

  1. Cruccu G, Di Stefano G, Truini A (2020) Trigeminal neuralgia. N Engl J Med 383(8):754–762

    Article  PubMed  Google Scholar 

  2. Montano N, Conforti G, Di Bonaventura R et al (2015) Advances in diagnosis and treatment of trigeminal neuralgia. Ther Clin Risk Manag 11:289–299

    Article  PubMed  PubMed Central  Google Scholar 

  3. Donertas-Ayaz B, Caudle RM (2023) Locus coeruleus-noradrenergic modulation of trigeminal pain: implications for trigeminal neuralgia and psychiatric comorbidities. Neurobiol Pain 13:100124

    Article  PubMed  PubMed Central  Google Scholar 

  4. Holland M, Noeller J, Buatti J et al (2015) The cost-effectiveness of Surgery for trigeminal neuralgia in surgically naïve patients: a retrospective study. Clin Neurol Neurosurg 137:34–37

    Article  PubMed  Google Scholar 

  5. Lynds R, Lyu C, Lyu GW et al (2017) Neuronal plasticity of trigeminal ganglia in mice following nerve injury. J Pain Res 10:349–357

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. De Córdoba JL, García Bach M, Isach N et al (2015) Percutaneous Balloon Compression for Trigeminal Neuralgia: imaging and technical aspects. Reg Anesth Pain Med 40(5):616–622

    Article  PubMed  Google Scholar 

  7. Wu H, Zhou J, Chen J et al (2019) Therapeutic efficacy and safety of radiofrequency ablation for the treatment of trigeminal neuralgia: a systematic review and meta-analysis. J Pain Res 12:423–441

    Article  PubMed  PubMed Central  Google Scholar 

  8. Patil S, Testarelli L (2021) Assessment of Growth factors, cytokines, and Cellular markers in saliva of patients with trigeminal Neuralgia. Molecules 26(10):2964

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Martin SL, Reid AJ, Verkhratsky A et al (2019) Gene expression changes in dorsal root ganglia following peripheral nerve injury: roles in inflammation, cell death and nociception. Neural Regen Res 14(6):939–947

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Zhu Y, Knolhoff BL, Meyer MA et al (2014) CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in Pancreatic cancer models. Cancer Res 74(18):5057–5069

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Xu C, Zheng H, Liu T et al (2021) Bioinformatics analysis identifies CSF1R as an essential gene mediating neuropathic pain - experimental research. Int J Surg 95:106140

    Article  PubMed  Google Scholar 

  12. Kilkenny C, Browne WJ, Cuthill IC et al (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. J Pharmacol Pharmacother 1(2):94–99

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhang SH, Yu J, Lou GD et al (2016) Widespread pain sensitization after partial infraorbital nerve transection in MRL/MPJ mice. Pain 157(3):740–749

    Article  PubMed  Google Scholar 

  14. Deuis JR, Dvorakova LS, Vetter I (2017) Methods used to Evaluate Pain behaviors in rodents. Front Mol Neurosci 10:284

    Article  PubMed  PubMed Central  Google Scholar 

  15. Tang Y, Liu L, Xu D et al (2018) Interaction between astrocytic colony stimulating factor and its receptor on microglia mediates central sensitization and behavioral hypersensitivity in chronic post ischemic pain model. Brain Behav Immun 68:248–260

    Article  PubMed  CAS  Google Scholar 

  16. Whitehead JL, Ohara PT, Tauscher An et al (2003) A procedure to deliver herpes simplex virus to the murine trigeminal ganglion. Brain Res Brain Res Protoc 12(1):60–66

    Article  PubMed  Google Scholar 

  17. Cannarile MA, Weisser M, Jacob W et al (2017) Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer 5(1):53

    Article  PubMed  PubMed Central  Google Scholar 

  18. Stanley ER, Chitu V (2014) CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol 6(6):a021857

    Article  PubMed  PubMed Central  Google Scholar 

  19. Thompson ML, Jimenez-Andrade JM, Chartier S et al (2015) Targeting cells of the myeloid lineage attenuates pain and Disease progression in a prostate model of Bone cancer. Pain 156(9):1692–1702

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Wang GYF, Shi XQ, Wu W et al (2018) Sustained and repeated mouth opening leads to development of painful temporomandibular disorders involving macrophage/microglia activation in mice. Pain 159(7):1277–1288

    Article  PubMed  Google Scholar 

  21. Karai L, Brown DC, Mannes AJ et al (2004) Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control. J Clin Invest 113(9):1344–1352

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Ju YY, Jiang M, Xu F et al (2021) CXCL10 and CXCR3 in the trigeminal ganglion contribute to Trigeminal Neuropathic Pain in mice. J Pain Res 14:41–51

    Article  PubMed  PubMed Central  Google Scholar 

  23. Thomas Cheng H (2010) Spinal cord mechanisms of chronic pain and clinical implications. Curr Pain Headache Rep 14(3):213–220

    Article  PubMed  Google Scholar 

  24. Ji RR, Nackley A, Huh Y et al (2018) Neuroinflammation and Central Sensitization in chronic and widespread Pain. Anesthesiology 129(2):343–366

    Article  PubMed  Google Scholar 

  25. Clark AK, Old EA, Malcangio M (2013) Neuropathic pain and cytokines: current perspectives. J Pain Res 6:803–814

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by the National Key Research and Development Program of China (No.2018YFC2001905).

Funding

This study was supported by the National Key Research and Development Program of China (No.2018YFC2001905).

Author information

Author notes

  1. Zile He, Chao Xu and Jiaqi Guo contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Peking University People’s Hospital, Xizhimen South Street 11, Beijing, 100044, China

    Zile He, Tianyu Liu, Yunpeng Zhang & Yi Feng

  2. Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China

    Chao Xu

  3. Shanghai Minhang Center for Disease Control and Prevention, Shanghai, China

    Jiaqi Guo

  4. Key Laboratory for Neuroscience, Ministry of Education/National Health Commission of China, Peking University, Xueyuan Road 38, Beijing, 100191, China

    Yi Feng

Authors
  1. Zile He
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  2. Chao Xu
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  3. Jiaqi Guo
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  4. Tianyu Liu
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  5. Yunpeng Zhang
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Contributions

Conceptualization: CX and YF; Methodology: ZH, CX and JG; Formal analysis and investigation: ZH, CX, JG, TL and YZ; Writing - original draft preparation: ZH and JG; Writing - review and editing: CX and YF; Funding acquisition: YF; Resources: YF; Supervision: YF. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Yi Feng.

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Ethical approval

This study was approved by the Ethics Committee of Peking University People’s Hospital (2021PHE009) and followed the role of the care and use of laboratory animals.

Competing interests

The authors declare no competing interests.

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He, Z., Xu, C., Guo, J. et al. The CSF1-CSF1R pathway in the trigeminal ganglion mediates trigeminal neuralgia via inflammatory responses in mice. Mol Biol Rep 51, 215 (2024). https://doi.org/10.1007/s11033-023-09149-y

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  • DOI: https://doi.org/10.1007/s11033-023-09149-y

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