NLRP3 inflammasome activation in sensory neurons promotes chronic inflammatory and osteoarthritis pain

IF 4.1 Q2 IMMUNOLOGY
Patrícia Silva Santos Ribeiro, Hanneke L D M Willemen, Sabine Versteeg, Christian Martin Gil, Niels Eijkelkamp
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Abstract

Abstract Pain is one of the most debilitating symptoms in rheumatic diseases. Pain often persists after total knee replacement in osteoarthritis, or when inflammation is minimal/absent in rheumatoid arthritis. This suggests that pain transitions to a chronic state independent of the original damage/inflammation. Mitochondrial dysfunction in the nervous system promotes chronic pain and is linked to NLRP3 inflammasome activation. Therefore, we investigated the role of mitochondrial dysfunction and NLRP3 inflammasome activation in the transition from acute to persistent inflammation-induced nociplastic pain and in persistent monoiodoacetate-induced osteoarthritis pain. Intraplantar injection of carrageenan in mice induced transient inflammatory pain that resolved within 7 days. A subsequent intraplantar PGE2 injection induced persistent mechanical hypersensitivity, while in naive mice it resolved within one day. Thus, this initial transient inflammation induced maladaptive nociceptor neuroplasticity, so-called hyperalgesic priming. At day 7, when mice were primed, expression of NLRP3 inflammasome pathway components were increased, and dorsal root ganglia neurons displayed signs of activated NLRP3 inflammasome. Inhibition of NLRP3 inflammasome with MCC950 prevented the transition from acute to chronic pain in this hyperalgesic priming model. In mice with persistent monoiodoacetate-induced osteoarthritis pain, neurons displayed signs of mitochondrial oxidative stress and NLRP3 inflammasome activation. Blocking NLRP3 inflammasome activity attenuated established osteoarthritis pain. In males, NLPR3 inhibition had longer lasting effects than in females. Overall, these data suggest that NLRP3 inflammasome activation in sensory neurons, potentially caused by neuronal oxidative stress, promotes development of persistent inflammatory and osteoarthritis pain. Therefore, targeting NLRP3 inflammasome pathway may be a promising approach to treat chronic pain.
感觉神经元中NLRP3炎性小体的激活促进慢性炎症和骨关节炎疼痛
疼痛是风湿病中最使人衰弱的症状之一。骨关节炎患者在全膝关节置换术后,或类风湿关节炎患者炎症轻微或无炎症时,疼痛常持续存在。这表明疼痛转变为一种独立于原始损伤/炎症的慢性状态。神经系统线粒体功能障碍促进慢性疼痛,并与NLRP3炎性体激活有关。因此,我们研究了线粒体功能障碍和NLRP3炎性小体激活在从急性到持续炎症诱导的伤害性疼痛和持续单碘乙酸诱导的骨关节炎疼痛的转变中的作用。小鼠足底注射角叉菜胶可引起短暂性炎性疼痛,7天内消退。随后足底注射PGE2诱导了持续的机械过敏,而在幼稚小鼠中,它在一天内消退。因此,这种初始的短暂炎症引起了伤害感受器神经可塑性不良,即所谓的痛觉过敏启动。在第7天,当小鼠被启动时,NLRP3炎症小体通路组分的表达增加,背根神经节神经元显示NLRP3炎症小体被激活的迹象。MCC950对NLRP3炎性体的抑制阻止了痛觉过敏启动模型中由急性疼痛向慢性疼痛的转变。在持续单碘酸盐诱导的骨关节炎疼痛小鼠中,神经元表现出线粒体氧化应激和NLRP3炎性体激活的迹象。阻断NLRP3炎性体活性可减轻已建立的骨关节炎疼痛。在男性中,NLPR3抑制作用比女性持久。总的来说,这些数据表明,感觉神经元中NLRP3炎性小体的激活,可能是由神经元氧化应激引起的,促进了持续性炎症和骨关节炎疼痛的发展。因此,靶向NLRP3炎性体通路可能是治疗慢性疼痛的一种有希望的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
5.00
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审稿时长
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