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 6

Impaired synaptic transmission and LTP induction in the spinal cord dorsal horn of Tlr3–/– mice but not Tlr7–/– mice.

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Impaired synaptic transmission and LTP induction in the spinal cord dors...
(A–F) Patch-clamp recording of sEPSCs in lamina II neurons in spinal cord slices. (A, C, and E) Traces of sEPSCs in spinal cord slices of WT and Tlr3–/– mice after (A) PIC (100 ng/ml) and (C) capsaicin (1 μM) treatment and (E) of WT and Tlr7–/– mice after capsaicin treatment (1 μM). (B, D, and F) sEPSC frequency and amplitude after the same treatments in A, C, and E. PIC and capsaicin only increase the frequency but not amplitude of sEPSC frequency in WT mice but not in Tlr3–/– mice. *P < 0.05, †P < 0.05, compared with WT pretreatment baseline; #P < 0.05, compared with WT-PIC or WT-capsaicin group, Student’s t test; n = 5–6 neurons. (G) Intrathecal (i.t.) PIC induces dose-dependent licking and biting in WT mice. *P < 0.05, Student’s t test, compared with vehicle; n = 6 mice. (H) Intrathecal PIC or (I) capsaicin induces licking and biting in WT mice but not Tlr3–/– mice. *P < 0.05, Student’s t test, compared with WT, n = 6 mice. (J and K) In vivo recordings of LTP of C-fiber–evoked filed potentials in the spinal cords of (J) Tlr3–/– and (K) Tlr7–/– mice and their corresponding WT controls. Note that spinal LTP is induced in Tlr7–/– mice but not in Tlr3–/– mice. *P < 0.05, compared with WT mice, 2-way repeated-measures ANOVA; n = 5 mice. All the data are mean ± SEM.