The innate immune system responds to infections that give rise to pain. How the innate immune system interacts with the sensory nervous system and contributes to pain is poorly understood. Here we report that hyperactivity of innate immunity primes and initiates pain states via the TLR2-interleukin-33 (IL-33) axis. Toll-like receptors (TLRs) are upregulated in the complete Freund’s adjuvant (CFA) pain model, and knockout of TLR2 abolishes CFA-induced pain. Selective activation of TLR2/6 triggers acute pain via upregulation of IL-33 in the hindpaw, dorsal root ganglia (DRG), and spinal cord in an NLRP3-dependent manner. The IL-33 increase further initiates priming of nociceptive neurons and pain states. Finally, blocking IL-33 receptors at the spinal level mediates analgesia during acute and chronic inflammatory pain, underscoring an important function of IL-33 in pain signaling. Collectively, our data reveal a critical role of the TLR2-IL-33 axis in innate immune activation for pain initiation and maintenance.

先天免疫系统会对引起疼痛的感染做出反应。先天免疫系统如何与感觉神经系统相互作用并导致疼痛还知之甚少。在这里，我们报告先天免疫的过度活跃通过 TLR2-白细胞介素-33 (IL-33) 轴引发和启动疼痛状态。Toll 样受体 (TLR) 在完全弗氏佐剂 (CFA) 疼痛模型中上调，敲除 TLR2 可消除 CFA 引起的疼痛。TLR2/6 的选择性激活通过以 NLRP3 依赖性方式上调后爪、背根神经节 (DRG) 和脊髓中的 IL-33 来触发急性疼痛。IL-33 的增加进一步启动了伤害感受神经元和疼痛状态的启动。最后，在脊髓水平阻断 IL-33 受体介导急性和慢性炎症性疼痛期间的镇痛，强调了 IL-33 在疼痛信号传导中的重要功能。总的来说，我们的数据揭示了 TLR2-IL-33 轴在先天免疫激活以引发和维持疼痛中的关键作用。