TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice

Tong Liu, Temugin Berta, Zhen Zhong Xu, Chul Kyu Park, Ling Zhang, Ning Lü, Qin Liu, Yang Liu, Yong Jing Gao, Yen Chin Liu, Qiufu Ma, Xinzhong Dong, Ru Rong Ji

Research output: Contribution to journalArticlepeer-review

109 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2195-2207
Number of pages13
JournalJournal of Clinical Investigation
Volume122
Issue number6
DOIs
Publication statusPublished - 2012 Jun 1

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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