Abstract
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.
Highlights
Low back pain (LBP) is a multifactorial disease,[7] and the disorder is strongly associated with intervertebral disc degeneration (IVDD), which is characterized by a homeostatic imbalance between anabolism and catabolism, including extracellular matrix (ECM) degradation[8,9] or nucleus pulposus (NP) cell survival.[10,11,12]
NP cells, we found that NLR pyrin domain containing 3 (NLRP3) and p20 expression were these published studies have indicated that melatonin partici- decreased in NP cells treated with different melatonin doses, pates in the IVDD process by regulating NLRP3 inflammasome with the lowest measured levels occurring at a dose of 1 mM
Melatonin ameliorates the progression of IVDD and LBP in vivo First, we established a rat IVDD model to determine whether melatonin exerts a protective effect during the progression of IVDD in vivo
Summary
Low back pain (LBP), one of the most common health problems, is a leading cause of disability worldwide and results in an enormous global burden to public health and the social economy, and ~84% of people experience LBP some point in their lifetime.[1,2,3,4,5,6] LBP is a multifactorial disease,[7] and the disorder is strongly associated with intervertebral disc degeneration (IVDD), which is characterized by a homeostatic imbalance between anabolism and catabolism, including extracellular matrix (ECM) degradation[8,9] or nucleus pulposus (NP) cell survival.[10,11,12] The intervertebral disc (IVD) is a special organ that consists of an outer fibrocartilaginous annulus fibrosus (AF) and an inner gel-like NP.[13,14] Inflammatory responses, which are induced by inflammatory cytokine overexpression, are a primary and important cause of IVDD. Recent studies have demonstrated that inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-1β, are strongly correlated with ECM degradation or NP cell survival.[15,16] a more profound understanding of the molecular mechanisms underlying inflammatory cytokine secretion might provide new therapeutic targets for IVDD
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