Activation of Different Heterodimers of TLR2 Distinctly Mediates Pain and Itch

doi:10.1016/j.neuroscience.2020.01.010

Neuroscience

Volume 429, 1 March 2020, Pages 245-255

https://doi.org/10.1016/j.neuroscience.2020.01.010 Get rights and content

Highlights

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TLR2 is expressed in different primary sensory neurons in TG and DRG.
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TLR2 is involved in inflammatory pain, acute and chronic itching.
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Activation of TLR2/TLR1 or TLR2/TLR6 produces distinct itch and pain behaviors.
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Activation of TLR2 increases [Ca²⁺]_i in DRG neurons via TRPV1 and TRPA1 channels.

Abstract

Toll-like receptors (TLRs) have been implicated in pain and itch regulation. TLR2, a TLR family member that detects microbial membrane components, has been implicated in pathologic pain. However, the role of TLR2 in pruritic and nociceptive responses has not been thoroughly investigated. In this study, we found that TLR2 was expressed in mouse dorsal root ganglia (DRG) and trigeminal ganglia (TG) neurons. Itch and pain behaviors, including histamine-dependent and histamine-independent acute itching, acetone/diethyl ether/water and 2,4-dinitrofluorobenzene-induced chronic itching and inflammatory pain, were largely attenuated in TLR2 knockout (KO) mice. The TLR2 agonist Pam3CSK4, which targets TLR2/1 heterodimers, evoked pain and itch behavior, whereas lipoteichoic acid (LTA) and zymosan, which recognize TLR2/6 heterodimers, produced only pain response. The TLR2 agonist-induced nociceptive and pruritic behaviors were largely diminished in transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) KO mice. Finally, Pam3Csk4 and zymosan increased the [Ca2⁺]_i in DRG neurons from wild-type mice. However, the enhancement of [Ca2⁺]_i was largely inhibited in the DRG neurons from TRPV1 and TRPA1 KO mice. Our results demonstrate that TLR2 is involved in different itch and pain behaviors through activating TLR1/TLR2 or TLR6/TLR2 heterodimers via TRPV1 and TRPA1 channels.

Introduction

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), initiating signals in innate and adaptive immunity (Akira et al., 2006). To date, more than 10 TLRs have been found in humans and mice (Kawai and Akira 2010). These receptors are expressed on cell or organelle membranes to sense different molecular patterns of viruses, bacteria, mycobacteria, fungi and parasites, participating in the immune response. Increasing evidence has shown that TLRs in the nervous system mediate pain and itch sensations (Liu et al., 2012b, Lacagnina et al., 2018). For example, TLR2, TLR4, TLR5, TLR7, TLR8 and TLR9 have been reported to induce neuropathic pain or spinal neuron plasticity (Kim et al., 2007, Christianson et al., 2011, Xu et al., 2015, Zhang et al., 2018, Luo et al., 2019). Particularly, recent studies have also demonstrated that TLR3, TLR4, and TLR7, which are expressed in a subset of pruriceptive and nociceptive neurons in the dorsal root ganglia (DRG) and trigeminal ganglia (TG), contribute to the processing of itch sensation (Liu et al., 2010, Liu et al., 2012a, Liu et al., 2016).

TLR2, a member of the TLR family, is expressed on the cell membrane for the detection of microbial membrane components and has been implicated in neuropathic pain processes (Kim et al., 2007, Kim et al., 2011a, Lim et al., 2013). Clinical data have indicated that TLR2 is highly expressed in the skin of individuals with chronic pruritic diseases such as atopic dermatitis and psoriasis (Panzer et al., 2014). However, whether TLR2 is involved in the regulation of pruritus has not been reported.

Among TLR family members, TLR2 recognizes the widest range of PAMPs derived from bacteria, fungi, parasites and viruses (Kawai and Akira 2010). Upon stimulation, while most of the other TLRs form homodimers between themselves, TLR2 mainly forms heterodimers with TLR1 and TLR6 on the cell membrane (Triantafilou et al., 2007, Oosting et al., 2011). The specificity of the TLR2 ligand is modulated by its heterodimeric partner, and different TLR2 agonists have been implicated in different signaling pathways and cell functions (Triantafilou et al., 2006, Oliveira-Nascimento et al., 2012, Vaisid and Kosower, 2013). However, whether activation of different TLR2 heterodimers induces distinct nociceptive/pruriceptive behaviors has not been demonstrated.

In the present study, we first revealed that TLR2 is expressed in small- to medium-sized primary sensory neurons in the DRG and TG and is primarily coexpressed with IB4 and slightly less with calcitonin gene-related peptide (CGRP), TRPV1 and TRPA1. Then, we demonstrated that TLR2 is involved in distinct itch and pain behaviors through activating TLR2/TLR1 or TLR2/TLR6 heterodimers. Finally, we demonstrated that itch and pain behaviors and the increased [Ca²⁺]_i in DRG neurons induced by TLR2 agonists depend on TRPV1 and TRPA1 channels.

Section snippets

Animal

C57BL/6 mice were purchased from SLAC Laboratory Animal Company (Shanghai, China). All mice, including TLR2 KO, TRPA1 KO and TRPV1 KO mice, were housed at a controlled temperature (22 ± 2 °C) and humidity (60–80%) under a 12-h/12-h light/dark cycle and provided food and water ad libitum. All experiments were performed in accordance with the guidelines for animals used in biological studies of Tongji University and were approved by the Animal Study Committee at Tongji University School of

TLR2 is expressed in small- to medium-sized primary sensory neurons in the DRG and TG

We first measured the expression of TLR2 in primary sensory neurons in the DRG and TG using immunofluorescence. TLR2 was mainly expressed in small (<300 µm²) and medium (300–700 µm²) DRG (91.23%, 1644 in 1802)) and TG (86.9%, 2112 in 2430) neurons in mice (Ichikawa et al., 2004, Ruscheweyh et al., 2007, Towne et al., 2009) (Fig. 1A, C, E, F). TLR2 KO mice showed few TLR2-positive neurons in the DRG and TG (Fig. 1B, D). Double immunostaining experiments further showed that TLR2 was coexpressed

Discussion

Increasing studies have shown that TLRs are expressed in not only immune cells but also neuronal and nonneuronal cells in the nervous system, contributing to inflammatory diseases. TLRs have been found in various types of cells, including glial cells and neurons, in the central and peripheral nervous systems. Recently, TLR3, 4, and 7 have been reported to be expressed in a subset of pruriceptive/nociceptive DRG and TG neurons in mice (Liu et al., 2010, Liu et al., 2012a, Taves and Ji, 2015).

Conflicts of interest

All authors have no conflicts of interest to declare.

Acknowledgments

We thank Prof. Xin-Ming Jia and Prof. Xiao-Ping Chen of Tongji University for the TLR2 KO mice. We also thank Prof. Zhen-Zhong Xu of Zhe-Jiang University for the TRPV1 and TRPA1 KO mice. This work was supported by the National Natural Science Foundation of China (31271182), the National Key R&D Program of China (2019YFA0110300) and Shanghai Changning District Committee of Science and Technology of China (CNKW2018Y08).

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^†: TT.W., XY.X contributed equally to this work.

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Research ArticleActivation of Different Heterodimers of TLR2 Distinctly Mediates Pain and Itch

Highlights

Abstract

Introduction

Section snippets

Animal

TLR2 is expressed in small- to medium-sized primary sensory neurons in the DRG and TG

Discussion

Conflicts of interest

Acknowledgments

Cell

Neuroscience

J Neurosci Methods

Pain

J Invest Dermatol

Acta Histochem

Cell

Immunity

Immunity

Life Sci

Cell

J Biol Chem

Pharmacol Ther

J Biol Chem

Neuron

Pain

Int Immunopharmacol

Biochim Biophys Acta

Immunobiology

Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice

Nat Med

Targeting toll-like receptor-4 (TLR4)-an emerging therapeutic target for persistent pain states

Pain

TLR4 enhanced histamine induced itch by TRPV1

Mol Brain

TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms

Proc Natl Acad Sci USA

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G Ital Dermatol Venereol

Structural biology of the Toll-like receptor family

Annu Rev Biochem

The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

Nat Immunol

Toll-like receptor 2 contributes to chemokine gene expression and macrophage infiltration in the dorsal root ganglia after peripheral nerve injury

Mol Pain

Analysis of cellular and behavioral responses to imiquimod reveals a unique itch pathway in transient receptor potential vanilloid 1 (TRPV1)-expressing neurons

Proc Natl Acad Sci USA

Research Article
Activation of Different Heterodimers of TLR2 Distinctly Mediates Pain and Itch