Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States.
Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, United States.
Pain. 2019 Aug;160(8):1794-1816. doi: 10.1097/j.pain.0000000000001555.
Postoperative pain management continues to be suboptimal because of the lack of effective nonopioid therapies and absence of understanding of sex-driven differences. Here, we asked how the NLRP3 inflammasome contributes to postoperative pain. Inflammasomes are mediators of the innate immune system that are responsible for activation and secretion of IL-1β upon stimulation by specific molecular signals. Peripheral IL-1β is known to contribute to the mechanical sensitization induced by surgical incision. However, it is not known which inflammasome mediates the IL-1β release after surgical incision. Among the 9 known inflammasomes, the NLRP3 inflammasome is ideally positioned to drive postoperative pain through IL-1β production because NLRP3 can be activated by factors that are released by incision. Here, we show that male mice that lack NLRP3 (NLRP3) recover from surgery-induced behavioral and neuronal mechanical sensitization faster and display less surgical site inflammation than mice expressing NLRP3 (wild-type). By contrast, female NLRP3 mice exhibit minimal attenuation of the postoperative mechanical hypersensitivity and no change in postoperative inflammation compared with wild-type controls. Sensory neuron-specific deletion of NLRP3 revealed that in males, NLRP3 expressed in non-neuronal cells and potentially sensory neurons drives postoperative pain. However, in females, only the NLRP3 that may be expressed in sensory neurons contributes to postoperative pain where the non-neuronal cell contribution is NLRP3 independent. This is the first evidence of a key role for NLRP3 in postoperative pain and reveals immune-mediated sex differences in postoperative pain.
由于缺乏有效的非阿片类治疗方法和对性别驱动差异的理解，术后疼痛管理仍然不尽如人意。在这里，我们探讨了 NLRP3 炎性体如何导致术后疼痛。炎性体是先天免疫系统的介质，负责在受到特定分子信号刺激时激活和分泌 IL-1β。已知外周 IL-1β有助于手术切口引起的机械致敏。然而，尚不清楚哪种炎性体介导手术切口后的 IL-1β 释放。在已知的 9 种炎性体中，NLRP3 炎性体通过产生 IL-1β 来驱动术后疼痛的能力最佳，因为 NLRP3 可以被切口释放的因素激活。在这里，我们发现缺乏 NLRP3（NLRP3）的雄性小鼠从手术引起的行为和神经元机械致敏中恢复得更快，并且与表达 NLRP3（野生型）的小鼠相比，手术部位的炎症更少。相比之下，与野生型对照相比，雌性 NLRP3 小鼠对术后机械性超敏反应的抑制作用极小，术后炎症无变化。感觉神经元特异性 NLRP3 缺失表明，在雄性中，非神经元细胞和潜在的感觉神经元中表达的 NLRP3 驱动术后疼痛。然而，在雌性中，只有可能在感觉神经元中表达的 NLRP3 有助于术后疼痛，而非神经元细胞的贡献与 NLRP3 无关。这是 NLRP3 在术后疼痛中起关键作用的第一个证据，并揭示了免疫介导的术后疼痛的性别差异。
