Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Orthopaedic Surgery, Puren Hospital of Wuhan, Wuhan University of Science and Technology, Wuhan, China.
Oxid Med Cell Longev. 2021 Jun 17;2021:5584447. doi: 10.1155/2021/5584447. eCollection 2021.
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 , 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 . These findings deepen the understanding of IDD pathogenesis and hold implications in unraveling therapeutic targets for IDD treatment.
椎间盘退行性变（IDD）是导致下腰痛的主要原因，在全球造成了沉重的社会负担。细胞焦亡是一种新发现的程序性细胞死亡形式，也参与了 IDD 进展过程中的髓核（NP）细胞。适度的自噬活性对 NP 细胞的存活至关重要，但自噬与细胞焦亡之间的关系尚不清楚。本研究旨在探讨自噬与细胞焦亡性细胞死亡之间的关系。测量了脂多糖（LPS）处理的人 NP 细胞中细胞焦亡执行者 GSDMD-N 的 N 端结构域和炎症相关蛋白。通过 siRNA 转染和化学药物抑制自噬加重了人 NP 细胞的细胞焦亡。重要的是，我们发现自噬-溶酶体途径而不是蛋白酶体途径介导 GSDMD-N 的降解，因为溶酶体功能障碍促进了细胞质 GSDMD-N 的积累。此外，P62/SQSTM1 与 GSDMD-N 共定位并介导其降解。在大鼠椎间盘 IDD 模型中证实，caspase-1 抑制剂 VX-765 的给药可以减少细胞焦亡，而 ATG5 敲低则显著加速了 IDD 的进展。总之，我们的研究表明，自噬通过 P62/SQSTM1 介导的降解机制来保护 LPS 诱导的人 NP 细胞发生细胞焦亡，而抑制细胞焦亡则延缓了 IDD 的进展。这些发现加深了对 IDD 发病机制的理解，并为揭示 IDD 治疗的治疗靶点提供了启示。
