Melatonin alleviates intervertebral disc degeneration by disrupting the IL-1β/NF-κB-NLRP3 inflammasome positive feedback loop

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.

Melatonin Protects Cholangiocytes from Oxidative Stress-Induced Proapoptotic and Proinflammatory Stimuli via miR-132 and miR-34

“…Furthermore, in this cellular model of PBC, the marker of oxidative stress, Nrf-2, was downregulated following cotreatment with melatonin. Consistent with our observations are reports showing that the inhibition of NF-κB signaling contributes to melatonin alleviating inflammation, downregulating mtROS production [ 51 ], and preventing invasiveness in HepG2 liver cancer cells [ 52 ].…”

A thermosensitive, reactive oxygen species-responsive, MR409-encapsulated hydrogel ameliorates disc degeneration in rats by inhibiting the secretory autophagy pathway

“…Also, an injectable hydrogel is advantageous for targeted in situ application. Since degenerated discs also exhibit ROS accumulation 48 , 49 , water soluble MR409 was loaded into ROS-responsive vesicles composed of a PPS-PEG amphiphilic polymer, and these loaded vesicles were then embedded in a thermosensitive PLGA-PEG-PLGA hydrogel for protection and controlled release 39 (Figure 5 A).…”

RNA-Binding Protein HuR Suppresses Inflammation and Promotes Extracellular Matrix Homeostasis via NKRF in Intervertebral Disc Degeneration

“…The results showed that various pathways were involved, among which NF-κB signaling pathway is most likely to participate in the regulatory effects of HuR on inflammation in IVDD ( Figure 3A). The NF-κB signaling pathway is a key regulator of inflammation (Liu T. et al, 2017); and evidences demonstrated that inhibition of NF-κB signaling pathway can delay the progression of IVDD (Liu T. et al, 2017;Chen F. et al, 2020). Thus, we focus on the NF-κB signaling pathway in further studies.…”