Autophagic Degradation of Gasdermin D Protects against Nucleus Pulposus Cell Pyroptosis and Retards Intervertebral Disc Degeneration In Vivo

Abstract

Intervertebral disc degeneration (IDD) is the primary culprit of low back pain and renders heavy social burden worldwide. Pyroptosis is a newly discovered form of programmed cell death, which is also involved in nucleus pulposus (NP) cells during IDD progression. Moderate autophagy activity is critical for NP cell survival, but its relationship with pyroptosis remains unknown. This study is aimed at investigating the relationship between autophagy and pyroptotic cell death. The pyroptosis executor N-terminal domain of gasdermin D (GSDMD-N) and inflammation-related proteins were measured in lipopolysaccharide- (LPS-) treated human NP cells. Inhibition of autophagy by siRNA transfection and chemical drugs aggravated human NP cell pyroptosis. Importantly, we found that the autophagy-lysosome pathway and not the proteasome pathway mediated the degradation of GSDMD-N as lysosome dysfunction promoted the accumulation of cytoplasmic GSDMD-N. Besides, P62/SQSTM1 colocalized with GSDMD-N and mediated its degradation. The administration of the caspase-1 inhibitor VX-765 could reduce cell pyroptosis as confirmed in a rat disc IDD model in vivo, whereas ATG5 knockdown significantly accelerated the progression of IDD. In conclusion, our study indicated that autophagy protects against LPS-induced human NP cell pyroptosis via a P62/SQSTM1-mediated degradation mechanism and the inhibition of pyroptosis retards IDD progression in vivo. These findings deepen the understanding of IDD pathogenesis and hold implications in unraveling therapeutic targets for IDD treatment.

Identification of SMIM1 and SEZ6L2 as Potential Biomarkers for Genes Associated with Intervertebral Disc Degeneration in Pyroptosis

“…IDD is a complex process in which resident pyroptosis promotes its development [ 33 , 34 ]. It has been identified that there is a considerable accumulation of inflammatory factors in IDD, leading to the accumulation of NLRP3, caspase-1, GSDMD, and other pyroptosis factors and eventually cell death [ 35 , 36 ]. Further investigation of the role of pyroptosis-related genes in IDD is consequently required.…”

Platelet-Derived Growth Factor-BB Inhibits Intervertebral Disc Degeneration via Suppressing Pyroptosis and Activating the MAPK Signaling Pathway

“…At present, more and more evidences show that pyrolysis plays an important role in the pathogenesis of degenerative disc disease. Therefore, we explored the effect of PDGF-BB on the pyrolysis of nucleus pulposus cells induced by IL-1β (Bai et al, 2020;Liao et al, 2021;Zhou et al, 2021). We found that PDGF-BB can effectively inhibit the activation of pyroptosis-related signals and the production of pyroptosis products in a concentration-dependent manner.…”

Role of Caspase Family in Intervertebral Disc Degeneration and Its Therapeutic Prospects

“…The integrity of the cell membrane is crucial for the release of pro-inflammatory factors, reducing the generation of GSDMD, and increasing its degradation can prevent the pore-forming damage to the cell membrane by GSDMD-N generated by cleavage. Through in vitro experiments, Liao et al [ 129 ] found that in an activated autophagy system, P62/SQSTM1 can selectively degrade GSDMD-N as an autophagy receptor, prevent GSDMD-N from accumulating on the cell membrane, and inhibit the pyroptosis of degenerated human NP cells. This correlates autophagy with pyroptosis and enhances the selective autophagy of pro-pyroptotic proteins.…”

“…These two inhibitors have been used in clinical studies in rheumatoid arthritis and OA [ 162 ]. In IVDD, delivery of VX-765 inhibits inflammasome activation and pyroptosis, thereby improving IVDD progression in vivo [ 129 ]. Although VX-765 has a good therapeutic effect on many diseases, it has certain toxic side effects and needs to be further improved for clinical applications.…”