Melatonin alleviates intervertebral disc degeneration by disrupting the IL-1β/NF-κB-NLRP3 inflammasome positive feedback loop
Melatonin alleviates intervertebral disc degeneration by disrupting the IL-1β/NF-κB-NLRP3 inflammasome positive feedback loop
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褪黑素通过破坏 IL-1 beta/NF-kappa B-NLRP3 炎性体正反馈环来减轻椎间盘退变
DOI：
10.1038/s41413-020-0087-2
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发表时间：
2020-02-18
期刊：
影响因子：
12.7
通讯作者：
Zheng, Zhaomin
中科院分区：
文献类型：
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作者：
Chen, Fan;Jiang, Guowei;Zheng, Zhaomin
炎症反应由炎性细胞因子（主要是白细胞介素（IL）-1 β）的过度表达诱导，并且是椎间盘退变（IVDD）的主要原因之一。NLR pyrin domain containing 3（NLRP 3）炎性体激活是IL-1 β的重要来源。褪黑素作为一种抗炎神经内分泌激素，在不同的病理生理状态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，需要更多的检查。首先，我们证明了褪黑激素延缓了大鼠针刺IVDD模型中IVDD的进展并缓解了IVDD相关的腰痛;此外，NLRP 3炎性小体激活（NLRP 3，p20和IL-1 β水平）在严重退化的人类椎间盘和大鼠IVDD模型中显著上调。随后，在用IL-1 β处理的髓核（NP）细胞中发现IL-1 β/NF-κ B-NLRP 3炎性体激活正反馈环。在这些细胞中，NLRP 3和p20的表达显著增加，NF-κ B B信号参与了这种调节，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-1 β/NF-κ B-NLRP 3炎性小体激活的正反馈回路。褪黑激素治疗通过抑制NF-κ B信号传导和下调mtROS产生来降低NLRP 3、p20和IL-1 β水平。最后，我们发现褪黑激素介导了体内IL-1 β正反馈环的破坏。在这项研究中，我们首次发现IL-1 β通过上调NLRP 3炎性小体激活来促进其自身表达。此外，褪黑激素破坏IL-1 β正反馈回路，可能是IVDD的潜在治疗剂。
The inflammatory response is induced by the overexpression of inflammatory cytokines, mainly interleukin (IL)-1 beta, 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-1 beta. 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-1 beta levels) was significantly upregulated in severely degenerated human discs and a rat IVDD model. Subsequently, an IL-1 beta/NF-kappa B-NLRP3 inflammasome activation positive feedback loop was found in nucleus pulposus (NP) cells that were treated with IL-1 beta. In these cells, expression of NLRP3 and p20 was significantly increased, NF-kappa B signaling was involved in this regulation, and mitochondrial reactive oxygen species (mtROS) production increased. Furthermore, we found that melatonin disrupted the IL-1 beta/NF-kappa B-NLRP3 inflammasome activation positive feedback loop in vitro and in vivo. Melatonin treatment decreased NLRP3, p20, and IL-1 beta levels by inhibiting NF-kappa B signaling and downregulating mtROS production. Finally, we showed that melatonin mediated the disruption of the positive feedback loop of IL-1 beta in vivo. In this study, we showed for the first time that IL-1 beta promotes its own expression by upregulating NLRP3 inflammasome activation. Furthermore, melatonin disrupts the IL-1 beta positive feedback loop and may be a potential therapeutic agent for IVDD.