Monocyte USP7-p65 axis mediates immune responses to the immunogenicity of nucleus pulposus

The nucleus pulposus (NP) of the intervertebral disc is an immune-privileged tissue. During intervertebral disc degeneration (IDD), this immune privilege is compromised, resulting in the exposure of NP components to the peripheral immune system, which in turn activates monocytes and elicits an immune response. In this study, we demonstrate that monocytes respond to NP immunogenicity by activating damage-associated molecular patterns (DAMPs), thereby initiating a sustained NF-κB-mediated inflammatory response in NP tissue and ultimately driving a vicious cycle of inflammation and oxidative stress within NP cells. Mechanistically, NP-derived immunogenic stimulation induces monocyte activation, accompanied by increased expression and nuclear translocation of the deubiquitinase USP7. USP7 promotes the accumulation and nuclear translocation of the NF-κB subunit p65 via a deubiquitination-dependent mechanism, leading to enhanced transcription of TNF-α, HMGB1, and IL-1β. These DAMP-associated cytokines further stimulate NP cells, resulting in upregulation of HMGB1, TNF-α, COX-2, IL-1β, and reactive oxygen species (ROS), along with a concomitant decrease in the antioxidant enzyme SOD2-collectively amplifying inflammation and oxidative stress within the NP microenvironment. Dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP)-qPCR demonstrated that knockdown of USP7 in monocytes significantly reduced p65 binding to the promoter regions of TNF-α, HMGB1, and IL-1β, thereby attenuating the downstream inflammatory and oxidative stress responses in NP cells. Together, these findings uncover a novel immune-inflammatory mechanism underlying IDD and highlight the USP7-mediated pathway in monocytes as a potential therapeutic target for modulating disc degeneration.