TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice
TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice
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DOI：
10.1172/jci45414
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发表时间：
2012-06-01
影响因子：
15.9
通讯作者：
Ji, Ru-Rong
中科院分区：
文献类型：
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作者：
Liu, Tong;Berta, Temugin;Ji, Ru-Rong
瘙痒，也被称为瘙痒，是几种皮肤病的常见、难治的症状，如特应性皮炎和干燥症。TLRs调节先天免疫和调节神经病理性疼痛，但它们在瘙痒中的作用尚不清楚。在这里，我们报告，在缺乏TLR3基因的小鼠中，组胺依赖和非组胺依赖的瘙痒原引起的抓挠行为显著减少。TLR3主要由背根神经节内的小型初级感觉神经元表达，它们共同表达瘙痒信号通路成分、瞬时受体电位亚型V1和胃泌素释放肽。值得注意的是，我们发现，用TLR3激动剂治疗可以诱导DRG神经元的内向电流和动作电位，并在WT小鼠中引发抓挠，但不会引起TLR3(-/-)小鼠的抓挠。此外，TLR3(-/-)小鼠脊髓切片的兴奋性突触传递和完整脊髓的长时程增强受到损害，而TLR7(-/-)小鼠则没有。因此，在TLR3(-/-)小鼠中，中枢敏感化驱动的疼痛超敏反应受到损害，但不是急性疼痛。此外，DRG中的TLR3基因敲除也可以减轻WT小鼠的瘙痒。最后，TLR3(-/-)小鼠在干燥皮肤条件下的慢性瘙痒显著减少。我们的研究结果表明，TLR3在调节感觉神经元兴奋性、脊髓突触传递和中枢敏化方面起着关键作用。TLR3可能成为开发止痒治疗的新靶点。
Itch, also known as pruritus, is a common, intractable symptom of several skin diseases, such as atopic dermatitis and xerosis. TLRs mediate innate immunity and regulate neuropathic pain, but their roles in pruritus are elusive. Here, we report that scratching behaviors induced by histamine-dependent and -independent pruritogens are markedly reduced in mice lacking the Tlr3 gene. TLR3 is expressed mainly by small-sized primary sensory neurons in dorsal root ganglions (DRGs) that coexpress the itch signaling pathway components transient receptor potential subtype V1 and gastrin-releasing peptide. Notably, we found that treatment with a TLR3 agonist induces inward currents and action potentials in DRG neurons and elicited scratching in WT mice but not Tlr3(-/-) mice. Furthermore, excitatory synaptic transmission in spinal cord slices and long-term potentiation in the intact spinal cord were impaired in Tlr3(-/-) mice but not Tlr7(-/-) mice. Consequently, central sensitization-driven pain hypersensitivity, but not acute pain, was impaired in Tlr3(-/-) mice. In addition, TLR3 knockdown in DRGs also attenuated pruritus in WT mice. Finally, chronic itch in a dry skin condition was substantially reduced in Tlr3(-/-) mice. Our findings demonstrate a critical role of TLR3 in regulating sensory neuronal excitability, spinal cord synaptic transmission, and central sensitization. TLR3 may serve as a new target for developing anti-itch treatment.