Toll-like receptor 7 contributes to neuropathic pain by activating NF-κB in primary sensory neurons.

Abstract

Toll like receptor 7 (TLR7) is expressed in neurons of the dorsal root ganglion (DRG), but whether it contributes to neuropathic pain is elusive. We found that peripheral nerve injury caused by ligation of the fourth lumbar (L4) spinal nerve (SNL) or chronic constriction injury of sciatic nerve led to a significant increase in the expression of TLR7 at mRNA and protein levels in mouse injured DRG. Blocking this increase through microinjection of the adeno-associated virus (AAV) 5 expressing TLR7 shRNA into the ipsilateral L4 DRG alleviated the SNL-induced mechanical, thermal and cold pain hypersensitivities in both male and female mice. This microinjection also attenuated the SNL-induced increases in the levels of phosphorylated extracellular signal-regulated kinase ½ (p-ERK1/2) and glial fibrillary acidic protein (GFAP) in L4 dorsal horn on the ipsilateral side during both development and maintenance periods. Conversely, mimicking this increase through microinjection of AAV5 expressing full-length TLR7 into unilateral L3/4 DRGs led to elevations in the amounts of p-ERK1/2 and GFAP in the dorsal horn, augmented responses to mechanical, thermal and cold stimuli, and induced the spontaneous pain on the ipsilateral side in the absence of SNL. Mechanistically, the increased TLR7 activated the NF-κB signaling pathway through promoting the translocation of p65 into the nucleus and phosphorylation of p65 in the nucleus from the injured DRG neurons. Our findings suggest that DRG TLR7 contributes to neuropathic pain by activating NF-κB in primary sensory neurons. TLR7 may be a potential target for therapeutic treatment of this disorder.

• Authors: Long He, Guang Han, Shaogen Wu, Shibin Du, Yang Zhang, Weili Liu, Baochun Jiang, Luyao Zhang, Shangzhou Xia, Shushan Jia, Stephen Hannaford, Ying Xu, Yuan-Xiang Tao
• Journal: Brain, behavior, and immunity (Brain Behav Immun) Vol. 87 Pg. 840-851 (07 2020) ISSN: 1090-2139 [Electronic] Netherlands
• PMID: 32205121 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Membrane Glycoproteins
• NF-kappa B
• Tlr7 protein, mouse
• Toll-Like Receptor 7

Topics

• Animals
• Female
• Ganglia, Spinal
• Hyperalgesia
• Male
• Membrane Glycoproteins
• Mice
• NF-kappa B
• Neuralgia
• Sensory Receptor Cells
• Toll-Like Receptor 7