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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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Research Article Neuroscience Article has an altmetric score of 5

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

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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 5

PIC induces inward current and action potentials in dissociated DRG neurons and elicits scratching in WT mice via TLR3 activation.

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PIC induces inward current and action potentials in dissociated DRG neur...
(A) Inward currents evoked by PIC and capsaicin (CAP) in dissociated small-sized DRG neurons from WT and Tlr3–/– mice. Note that PIC fails to induce inward currents in Tlr3–/– mice. (B) Dose-dependent inward currents induced by PIC. The number of responsive neurons is indicated on the top of each bar. (C) A combination of patch-clamp recording and single-cell RT-PCR in small-sized DRG neurons shows that all 4 neurons (out of 10) that respond to PIC (200 ng/ml) also express Tlr3 mRNA. (D) Action potentials evoked by PIC and capsaicin in DRG neurons from WT and Tlr3–/– mice. Note that PIC does not induce action potentials in Tlr3–/– mice (n = 18 neurons). (E) Intradermal PIC induces dose-dependent scratching in WT mice. *P < 0.05, compared with vehicle; n = 6 mice. (F) Intradermal PIC induces scratching in WT mice but not Tlr3–/– mice. *P < 0.05, compared with WT, Student’s t test; n = 6 mice. (G) Inward currents evoked by the extracted total RNAs, PIC, and capsaicin in small-sized DRG neurons from WT and Tlr3–/– mice. (H) Dose-dependent inward currents induced by the total RNAs. The number of responsive neurons is indicated on the top of each bar. All the data are mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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