2020.04.03 Journal Club

Activation of Different Heterodimers of TLR2 Distinctly Mediates Pain and Itch

Ting-Ting Wang, a,c,dy Xian-Yun Xu, a,b,cy Wei Lin, e Dan-Dan Hu, a,b,c Wu Shi, a,b,c Xin Jia, a,b,c Hui Wang, a Ning-Jing Song, d Yu-Qiu Zhang e and Ling Zhang a,b,c*

a The First Rehabilitation Hospital of Shanghai, Tongji University School of Medicine, Shanghai 200090, China
b Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji

Hospital, School of Medicine, Tongji University, Shanghai, 200065, China

c Department of Anatomy and Histology, Tongji University School of Medicine, Shanghai 200092, China

d Department of Dermatology, Tongren Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200336, China

e State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Translational Neuroscience, Institutes of Brain Science, Fudan University, Shanghai 200032, China

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-dini trofluorobenzene-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. ! 2020 IBRO. Published by Elsevier Ltd. All rights reserved.

Key words: TLR2, pain, itch, TRPV1, TRPA1.