Department of Physiology and Pharmacology, Cumming School of Medicine.
Inflammation Research Network-Snyder Institute for Chronic Diseases, Cumming School of Medicine, and.
J Clin Invest. 2024 Mar 19;134(9):e176474. doi: 10.1172/JCI176474.
Inflammation and pain are intertwined responses to injury, infection, or chronic diseases. While acute inflammation is essential in determining pain resolution and opioid analgesia, maladaptive processes occurring during resolution can lead to the transition to chronic pain. Here we found that inflammation activates the cytosolic DNA-sensing protein stimulator of IFN genes (STING) in dorsal root ganglion nociceptors. Neuronal activation of STING promotes signaling through TANK-binding kinase 1 (TBK1) and triggers an IFN-β response that mediates pain resolution. Notably, we found that mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia through a KChIP1-Kv4.3 regulation. Our findings reveal a role of IFN-regulated genes and KChIP1 downstream of STING in the resolution of inflammatory pain.
炎症和疼痛是对损伤、感染或慢性疾病的交织反应。虽然急性炎症对于确定疼痛缓解和阿片类镇痛药的效果至关重要，但在缓解过程中发生的适应性不良过程可能导致慢性疼痛的发生。在这里，我们发现炎症会激活背根神经节伤害感受器中的细胞质 DNA 感应蛋白干扰素基因刺激因子（STING）。STING 在神经元中的激活促进了 TANK 结合激酶 1（TBK1）的信号转导，并引发了介导疼痛缓解的 IFN-β 反应。值得注意的是，我们发现表达 STING 伤害感受器特异性获得性功能突变的小鼠表现出 IFN 基因特征，该特征通过 KChIP1-Kv4.3 调节降低伤害感受器兴奋性和炎症性痛觉过敏。我们的发现揭示了 IFN 调节基因和 STING 下游的 KChIP1 在炎症性疼痛缓解中的作用。
