The inflammatory response is induced by the overexpression of inflammatory cytokines, mainly interleukin (IL)-1β, and is one of the main causes of intervertebral disc degeneration (IVDD). NLR pyrin domain containing 3 (NLRP3) inflammasome activation is an important source of IL-1β. As an anti-inflammatory neuroendocrine hormone, melatonin plays various roles in different pathophysiological conditions. However, its roles in IVDD are still not well understood and require more examination. First, we demonstrated that melatonin delayed the progression of IVDD and relieved IVDD-related low back pain in a rat needle puncture IVDD model; moreover, NLRP3 inflammasome activation (NLRP3, p20, and IL-1β levels) was significantly upregulated in severely degenerated human discs and a rat IVDD model. Subsequently, an IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop was found in nucleus pulposus (NP) cells that were treated with IL-1β. In these cells, expression of NLRP3 and p20 was significantly increased, NF-κB signaling was involved in this regulation, and mitochondrial reactive oxygen species (mtROS) production increased. Furthermore, we found that melatonin disrupted the IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop in vitro and in vivo. Melatonin treatment decreased NLRP3, p20, and IL-1β levels by inhibiting NF-κB signaling and downregulating mtROS production. Finally, we showed that melatonin mediated the disruption of the positive feedback loop of IL-1β in vivo. In this study, we showed for the first time that IL-1β promotes its own expression by upregulating NLRP3 inflammasome activation. Furthermore, melatonin disrupts the IL-1β positive feedback loop and may be a potential therapeutic agent for IVDD.

炎症反应是由炎症细胞因子过度表达引起的，主要是白细胞介素（IL）-1β，是椎间盘退变（IVDD）的主要原因之一。含 NLR 吡啶结构域 3 (NLRP3) 炎性体激活是 IL-1β 的重要来源。作为一种抗炎神经内分泌激素，褪黑激素在不同的病理生理条件下发挥着不同的作用。然而，它在 IVDD 中的作用仍然没有得到很好的理解，需要更多的研究。首先，我们在大鼠针刺 IVDD 模型中证明，褪黑素可延缓 IVDD 的进展并缓解 IVDD 相关的腰痛；此外，在严重退化的人类椎间盘和大鼠 IVDD 模型中，NLRP3 炎症小体激活（NLRP3、p20 和 IL-1β 水平）显着上调。随后，在用 IL-1β 处理的髓核 (NP) 细胞中发现了 IL-1β/NF-κB-NLRP3 炎症小体激活正反馈环。在这些细胞中，NLRP3 和 p20 的表达显着增加，NF-κB 信号传导参与了这种调节，并且线粒体活性氧 (mtROS) 的产生增加。此外，我们发现褪黑激素在体外和体内破坏了 IL-1β/NF-κB-NLRP3 炎症小体激活正反馈环。褪黑激素治疗通过抑制 NF-κB 信号传导和下调 mtROS 产生来降低 NLRP3、p20 和 IL-1β 水平。最后，我们发现褪黑激素介导了体内IL-1β正反馈回路的破坏。在这项研究中，我们首次证明IL-1β通过上调NLRP3炎性体激活来促进其自身表达。此外，褪黑激素会破坏 IL-1β 正反馈环，可能是 IVDD 的潜在治疗剂。