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.

中文翻译：

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TLR2 不同异二聚体的激活明显介导疼痛和瘙痒。

Toll 样受体 (TLR) 与疼痛和瘙痒调节有关。TLR2 是检测微生物膜成分的 TLR 家族成员，与病理性疼痛有关。然而，尚未彻底研究 TLR2 在瘙痒和伤害性反应中的作用。在这项研究中，我们发现 TLR2 在小鼠背根神经节 (DRG) 和三叉神经节 (TG) 神经元中表达。TLR2 基因敲除 (KO) 小鼠的瘙痒和疼痛行为，包括组胺依赖性和组胺非依赖性急性瘙痒、丙酮/乙醚/水和 2,4-二硝基氟苯诱导的慢性瘙痒和炎性疼痛，在很大程度上得到缓解。靶向 TLR2/1 异二聚体的 TLR2 激动剂 Pam3CSK4 引起疼痛和瘙痒行为，而识别 TLR2/6 异二聚体的脂磷壁酸 (LTA) 和酵母聚糖，只产生疼痛反应。TLR2 激动剂诱导的伤害性和瘙痒行为在瞬时受体电位香草素 1 (TRPV1) 和瞬时受体电位锚蛋白 1 (TRPA1) KO 小鼠中大大减少。最后，Pam3Csk4 和酵母聚糖增加了野生型小鼠背根神经节神经元中的 [Ca2+]i。然而，[Ca2+]i 的增强在 TRPV1 和 TRPA1 KO 小鼠的 DRG 神经元中受到很大抑制。我们的研究结果表明，TLR2 通过 TRPV1 和 TRPA1 通道激活 TLR1/TLR2 或 TLR6/TLR2 异二聚体参与不同的瘙痒和疼痛行为。Pam3Csk4 和酵母聚糖增加了野生型小鼠背根神经节神经元中的 [Ca2+]i。然而，[Ca2+]i 的增强在 TRPV1 和 TRPA1 KO 小鼠的 DRG 神经元中受到很大抑制。我们的研究结果表明，TLR2 通过 TRPV1 和 TRPA1 通道激活 TLR1/TLR2 或 TLR6/TLR2 异二聚体参与不同的瘙痒和疼痛行为。Pam3Csk4 和酵母聚糖增加了野生型小鼠背根神经节神经元中的 [Ca2+]i。然而，[Ca2+]i 的增强在 TRPV1 和 TRPA1 KO 小鼠的 DRG 神经元中受到很大抑制。我们的研究结果表明，TLR2 通过 TRPV1 和 TRPA1 通道激活 TLR1/TLR2 或 TLR6/TLR2 异二聚体参与不同的瘙痒和疼痛行为。