TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice
Tong Liu, … , Xinzhong Dong, Ru-Rong Ji
Tong Liu, … , Xinzhong Dong, Ru-Rong Ji
Published May 8, 2012
Citation Information: J Clin Invest. 2012;122(6):2195-2207. https://doi.org/10.1172/JCI45414.
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TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice

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.

Authors

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

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Figure 7

TLR3 signaling in DRGs of WT adult mice is required for pruritus.

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TLR3 signaling in DRGs of WT adult mice is required for pruritus. (A) Kn...
(A) Knockdown of TLR3 expression in DRGs after intrathecal injections of Tlr3 AS-ODNs (10 μg daily for 5 days). The lanes ran on the same gel but were noncontiguous. Note that both TLR3 protein and mRNA levels but not Tlr4 mRNA levels in DRGs are decreased after AS-ODN treatment, revealed by Western blotting or quantitative PCR. *P < 0.05, Student’s t test; n = 4 mice. (B) Inhibition of compound 48/80– and CQ-induced scratching after treatment with TLR3 AS-ODNs. MM, mismatch oligodeoxynucleotides. *P < 0.05, Student t test; n = 5 mice. (C) No effects of TLR3 AS-ODNs on basal heat sensitivity (n = 5 mice). (D) Quantitative PCR reveals knockdown of Tlr3 but not Tlr7 and Tlr9 mRNA expression in DRGs after intrathecal injections of Tlr3-targeting siRNA (3 μg daily for 3 days). *P < 0.05, Student’s t test; n = 5 mice. (E) Inhibition of CQ-induced scratching after siRNA treatment. *P < 0.05, Student t test; n = 5 mice. (F) Intrathecal inhibition of TLR3 signaling with a peptide inhibitor of TRIF reduces scratching in mice. *P < 0.05, Student’s t test; n = 5 mice. All the data are mean ± SEM.