This study investigates the effect of prolonged nuclear factor κB (NF-κB) activation on intervertebral disc (IVD) degeneration using an inducible mouse model. The researchers targeted cells expressing aggrecan, a key component of the IVD extracellular matrix, to activate the canonical NF-κB pathway. Prolonged NF-κB activation led to severe structural degeneration of the caudal IVD, characterized by increased gene expression of inflammatory molecules (Il1b, Cox2, Il6, and Nos2), chemokines (Mcp1 and Mif), and catabolic enzymes (Mmp3, Mmp9, and Adamts4). The study observed increased recruitment and activation of proinflammatory (F4/80+CD38+) and inflammatory resolving (F4/80+CD206+) macrophages within the caudal IVD. The secretome of inflamed caudal IVD cells promoted macrophage migration and inflammatory activation. In contrast, lumbar IVDs did not exhibit significant phenotypic changes, suggesting regional spinal differences in response to inflammatory genetic overactivation. The findings suggest that prolonged NF-κB activation can induce severe IVD degeneration through increased inflammatory cytokines, chemotactic proteins, catabolic enzymes, and macrophage recruitment and activation.This study investigates the effect of prolonged nuclear factor κB (NF-κB) activation on intervertebral disc (IVD) degeneration using an inducible mouse model. The researchers targeted cells expressing aggrecan, a key component of the IVD extracellular matrix, to activate the canonical NF-κB pathway. Prolonged NF-κB activation led to severe structural degeneration of the caudal IVD, characterized by increased gene expression of inflammatory molecules (Il1b, Cox2, Il6, and Nos2), chemokines (Mcp1 and Mif), and catabolic enzymes (Mmp3, Mmp9, and Adamts4). The study observed increased recruitment and activation of proinflammatory (F4/80+CD38+) and inflammatory resolving (F4/80+CD206+) macrophages within the caudal IVD. The secretome of inflamed caudal IVD cells promoted macrophage migration and inflammatory activation. In contrast, lumbar IVDs did not exhibit significant phenotypic changes, suggesting regional spinal differences in response to inflammatory genetic overactivation. The findings suggest that prolonged NF-κB activation can induce severe IVD degeneration through increased inflammatory cytokines, chemotactic proteins, catabolic enzymes, and macrophage recruitment and activation.