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
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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Research Article Neuroscience

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 8

TLR3 is essential for dry skin–induced chronic itch.

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TLR3 is essential for dry skin–induced chronic itch. (A) Spontaneous scr...
(A) Spontaneous scratching induced by acetone and diethyether (1:1) following by water (AEW, twice a day for 7 days) on day 8 and 9 in WT and Tlr3–/– mice. *P < 0.05. (B) Real-time quantitative RT-PCR analysis showing TLR3 upregulation in skin but not DRGs of WT mice after AEW treatment. *P < 0.05. (C and D) Real-time quantitative RT-PCR analysis showing that AEW-induced upregulation of (C) NGF but not (D) TNF-α in the dry skin is abrogated in Tlr3–/– mice. *P < 0.05, #P < 0.05. (E) ELISA analysis showing that AEW-induced upregulation of histamine in skin is not altered in Tlr3–/– mice. *P < 0.05, compared with vehicle control (CTRL). (F) Intradermal injection of PIC enhances AEW-induced spontaneous scratching, which is abrogated in Tlr3–/– mice. *P < 0.05, Student’s t test; n = 5 mice in all cases. All the data are mean ± SEM.