Abstract
Our previous study verified the occurrence of Propionibacterium acnes (P. acnes), a low-virulence anaerobic bacterium, latently residing in degenerated intervertebral discs (IVDs), and the infection had a strong association with IVD degeneration. We explored whether P. acnes induces nucleus pulposus cell (NPC) pyroptosis, a more dangerous cell death process than apoptosis, and accelerates IVD degeneration via the pyroptotic products interleukin- (IL-) 1β and IL-18. After coculturing with P. acnes, human NPCs showed significant upregulation of NOD-like receptor 3 (NLRP3), cleaved IL-1β, cleaved caspase-1, and cleaved gasdermin D in response to the overexpression of IL-1β and IL-18 in a time- and dose-dependent manner. In addition, the gene expression of inflammatory factors and catabolic enzymes significantly increased in normal NPCs when cocultured with pyroptotic NPCs in a transwell system, and the adverse effects were inhibited when NPC pyroptosis was suppressed. Furthermore, inoculation of P. acnes into the IVDs of rats caused significant pyroptosis of NPCs and remarkable IVD degeneration. Finally, coculture of NPCs with P. acnes induced the overexpression of reactive oxygen species (ROS) and NLRP3, while inhibition of both factors reduced NPC pyroptosis. Therefore, P. acnes induces NPC pyroptosis via the ROS-NLRP3 signaling pathway, and the pyroptotic NPCs cause an IVD degeneration cascade. Targeting the P. acnes-induced pyroptosis of NPCs may become an alternative treatment strategy for IVD degeneration in the future.
Highlights
Intervertebral disc (IVD) degeneration is a serious public health problem
When P. acnes was cocultured with nucleus pulposus cells (NPCs) for different durations and multiplicity of infection (MOI), the NPCs showed remarkable pyroptosis
We previously reported that P. acnes, a low-virulence anaerobic bacterium that latently resides in IVDs, induced the pyroptosis of NPCs
Summary
Intervertebral disc (IVD) degeneration is a serious public health problem. A variety of clinical symptoms are caused by IVD degeneration, such as sciatica, lower back pain, and physical dysfunction, which significantly reduce the quality of life and work productivity of patients and increase the burden on the medical system [1]. There have been several hypothetical explanations for IVD degeneration: excessive axial or shear force, biochemical factors, gene diversity, and low-virulence anaerobic bacterial infection [1]. Since the first report by Stirling et al in 2001 [2], the pooled bacterial infection rate of IVDs over the past decade has been 25.3% [3]. Of the various infecting lowvirulence anaerobic bacteria, Propionibacterium acnes is the most important for IVD degeneration, with an IVD infection rate of around 15.5% [3]. Our previous study reported the infection rate of P. acnes to be 26.25% within degenerated IVDs, and this bacterial infection has a strong clinical association with IVD herniation in younger patients [4, 5]
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