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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 4

Expression of TLR3 in a subset of small-sized DRG neurons.

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Expression of TLR3 in a subset of small-sized DRG neurons.
(A) Single-ce...
(A) Single-cell RT-PCR analysis from dissociated small-sized DRG neurons showing the distinct and overlapped distribution patterns of TLR3 and TLR7 in DRG neurons. The lanes were run on the same gel but were noncontiguous. M, marker; NC, negative control. (B) Single-cell RT-PCR analysis from dissociated small-sized DRG neurons showing colocalization of TLR3 with TPRV1 and GRP. Similar results were obtained from 3 independent experiments in 30 cells collected from different animals. (C) Double immunostaining in DRGs showing co-colocalization of TLR3 and GRP. Red and yellow arrows indicate GRP+ only and double-labeled neurons, respectively. Scale bars: 50 μm. (D) Cell size distribution frequency of TLR3+ and GRP+ neurons. (E) Double immunostaining in cultured DRG neurons showing co-colocalization of TLR3 with TRPV1 but not with NF200. Green arrows indicate NF200+ or TRPV1+ neurons, red arrows indicate TLR3+ neurons, and yellow allows indicate double-labeled neurons. Scale bars: 50 μm. (F) A Venn diagram showing the relationship of TLR3+, GRP+, and TRPV1+ populations in a DRG. Note that all TLR3+ cells also express GRP and TRPV1.

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

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