Intervertebral disc degeneration (IVDD), a leading cause of low back pain, is primarily mediated by inflammatory responses induced by pro-inflammatory cytokines such IL-1β. New findings suggest that IL-1β can promote its own expression in IVDD via a positive feedback loop involving the NLRP3 inflammasome, which can be targeted therapeutically with melatonin.
The NLRP3 inflammasome is a known source of IL-1β and has been implicated in several inflammatory diseases. In the new study, IL-1β upregulated the expression of NLRP3 and p20 (components of the NLRP3 inflammasome) in vitro in nucleus pulposus (NP) cells (cells that make up part of the intervertebral disc). Furthermore, NLRP3 inflammasome activation (including the expression of NLRP3, p20 and IL-1β) was upregulated in the degenerative discs of patients with IVDD and in rats with annulus fibrosus puncture-induced IVDD (a rat model of IVDD).
Further experiments found that IL-1β could induce both NLRP3 inflammasome priming and activation in NP cells by upregulating nuclear factor-κB (NF-κB) signalling. Indeed, treatment with an inhibitor of the NF-κB pathway (SM7368) inhibited IL-1β-induced upregulation of NLRP3 expression. IL-1β could also promote the production of mitochondrial reactive oxygen species (mtROS) in these cells in vitro.
Melatonin is a neuroendocrine hormone with various functions, including anti-inflammatory activities. In vitro treatment of NP cells with melatonin inhibited the positive feedback loop of IL-1β, including IL-1β -induced NF-κB signalling, NLRP3 inflammasome priming and activation, and mtROS production.
Notably, in the rat model of IVDD, treatment with melatonin also disrupted this positive feedback loop, alleviating the progression of IVDD and IVDD-related low back pain.
melatonin inhibited the positive feedback loop of IL-1β
“We plan to knock down NLRP3 to further verify the mechanisms of IL-1β metabolism,” explains Jianru Wang, co-corresponding author of the study. “We think that melatonin could be a promising therapeutic strategy for patients with IVDD and low back pain,” continues co-corresponding author Zhaomin Zheng.
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Chen, F. et al. Melatonin alleviates intervertebral disc degeneration by disrupting the IL-1β/NF-κB-NLRP3 inflammasome positive feedback loop. Bone Res. 8, 10 (2020)
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McHugh, J. Targeting IL-1β expression in IVDD. Nat Rev Rheumatol 16, 188 (2020). https://doi.org/10.1038/s41584-020-0403-7
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DOI: https://doi.org/10.1038/s41584-020-0403-7
