Role of Pyroptosis in Intervertebral Disc Degeneration and Its Therapeutic Implications

Abstract

Intervertebral disc degeneration (IDD), a progressive and multifactorial pathological process, is predominantly associated with low back pain and permanent disability. Pyroptosis is a type of lytic programmed cell death triggered by the activation of inflammasomes and caspases. Unlike apoptosis, pyroptosis is characterized by the rupture of the plasma membrane and the release of inflammatory mediators, accelerating the destruction of the extracellular matrix (ECM). Recent studies have shown that pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis in nucleus pulposus (NP) cells is activated in the progression of IDD. Furthermore, targeting pyroptosis in IDD demonstrates the excellent capacity of ECM remodeling and its anti-inflammatory properties, suggesting that pyroptosis is involved in the IDD process. In this review, we briefly summarize the molecular mechanism of pyroptosis and the pathogenesis of IDD. We also focus on the role of pyroptosis in the pathological progress of IDD and its targeted therapeutic application.

Keywords: NLRP3 inflammasome; intervertebral disc degeneration; nucleus pulposus; pyroptosis.

Figure 1

Pyroptosis pathway. The canonical inflammasome-induced pyroptosis pathway (taken NLRP3 inflammasome pathway) begins with the interaction between receptors and ligands. Then, the NF-κB signal is activated and increases the expression of the NLRP3 inflammasome. Meanwhile, activation signals, including various disturbances, improve the assembly of the NLRP3 inflammasome. Then, the assembled NLPR3 activates caspase-1 to mature IL-18 and IL-1β. The noncanonical inflammasome-induced pyroptosis is mediated by LPS to activate caspase-4/5/11 to cleave GSDMD. In other ways, different cells activate the gasdermin family through caspase-dependent or caspase-independent pathways, which eventually lead to cell expansion, membrane perforation, and the release of cytoplasmic content. IL: interleukin; TNF-α: tumor necrosis factor-α; PAMPs: pathogen-associated molecular patterns; DAMPs: damage-associated molecular patterns; TLRs: toll-like receptors; ROS: reactive oxygen species; ER: endoplasmic reticulum; LPS: lipopolysaccharide; GSDMD: gasdermin D; GzmA: granzyme A; GzmB: granzyme B; CAR-T: chimeric antigen receptor T.

Figure 2

Changes in normal and degenerative intervertebral discs. The intervertebral disc is composed of nucleus pulposus (NP), annulus fibrosus (AF), and endplate (EP), together constituting a closed buffer system against stress. While in IDD, cell death, ECM degradation, and secondary verification aggravate the vicious cycle, which is closely associated with pyroptosis. ECM: extracellular matrix; ADAMTS: a disintegrin and metalloproteinase with thrombospondin motifs; MMPs: matrix metalloproteinases.