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/or 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.

中文翻译：

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Toll 样受体 7 通过激活初级感觉神经元中的 NF-κB 导致神经性疼痛

Toll 样受体 7 (TLR7) 在背根神经节 (DRG) 的神经元中表达，但它是否会导致神经性疼痛尚不清楚。我们发现第四腰椎 (L4) 脊神经 (SNL) 结扎或坐骨神经慢性缩窄性损伤引起的周围神经损伤导致小鼠损伤 DRG 中 TLR7 在 mRNA 和/或蛋白水平上的表达显着增加。通过将表达 TLR7 shRNA 的腺相关病毒 (AAV) 5 显微注射到同侧 L4 DRG 中来阻断这种增加，减轻了 SNL 诱导的雄性和雌性小鼠的机械、热和冷痛超敏反应。在发育和维持期间，这种显微注射还减弱了 SNL 诱导的同侧 L4 背角磷酸化细胞外信号调节激酶 ½ (p-ERK1/2) 和胶质纤维酸性蛋白 (GFAP) 水平的增加。相反，通过将表达全长 TLR7 的 AAV5 显微注射到单侧 L3/4 DRG 中来模拟这种增加，导致背角中 p-ERK1/2 和 GFAP 的量升高，增强了对机械、热和冷刺激的反应，以及在没有 SNL 的情况下诱导同侧的自发性疼痛。从机制上讲，增加的 TLR7 通过促进 p65 易位进入细胞核和 p65 从受伤的 DRG 神经元磷酸化在细胞核中激活 NF-κB 信号通路。我们的研究结果表明，DRG TLR7 通过激活初级感觉神经元中的 NF-κB 导致神经性疼痛。TLR7 可能是治疗这种疾病的潜在靶点。