先天免疫活性亢进通过 TLR2-IL-33 介导的神经免疫串扰引发疼痛。
Hyperactivity of Innate Immunity Triggers Pain via TLR2-IL-33-Mediated Neuroimmune Crosstalk.
机构信息
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
出版信息
Cell Rep. 2020 Oct 6;33(1):108233. doi: 10.1016/j.celrep.2020.108233.
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.
先天性免疫系统对引起疼痛的感染作出反应。先天性免疫系统如何与感觉神经系统相互作用并导致疼痛，这一点我们还知之甚少。在这里，我们报告称，先天免疫过度活跃通过 TLR2-白细胞介素 33（IL-33）轴引发和启动疼痛状态。在完全弗氏佐剂（CFA）疼痛模型中，Toll 样受体（TLR）上调，并且 TLR2 的基因敲除可消除 CFA 诱导的疼痛。TLR2/6 的选择性激活通过 NLRP3 依赖性方式在上足、背根神经节（DRG）和脊髓中上调白细胞介素 33 引发急性疼痛。IL-33 的增加进一步引发伤害感受神经元的致敏和疼痛状态。最后，在急性和慢性炎症性疼痛期间，在脊髓水平阻断 IL-33 受体可介导镇痛，这突出了 IL-33 在疼痛信号传导中的重要功能。总之，我们的数据揭示了 TLR2-白细胞介素 33 轴在先天免疫激活引发和维持疼痛中的关键作用。
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