THBS1 ⁺ Macrophages Exacerbate Modic Changes via SDC4‐Dependent Activation of NLRP3 Inflammasome

ABSTRACT

Modic changes (MCs) in the lumbar vertebral endplates are a common imaging finding in patients with low back pain. Their pathogenesis and progression are closely linked to the local immune microenvironment, underscoring the need to investigate the immunomodulatory mechanisms involved in MCs. Here, we identified the THBS1 ⁺ macrophages displaying a strongly pro‐inflammatory phenotype. The THBS1 ⁺ macrophages were enriched at lesion sites in both human lumbar MCs specimens and the C. acnes‐induced mouse model of MC. In vitro, C. acnes and its key metabolites promoted THBS1 expression in macrophages via Toll‐like receptor (TLR) signaling, while TLR inhibition alleviated MCs by suppressing this macrophage subset. Notably, conditional knockout of THBS1 in macrophages effectively attenuated C. acnes‐induced MCs progression. Mechanistically, we identified syndecan‐4 (SDC4) on endplate chondrocytes as a functional receptor for macrophage‐derived THBS1. THBS1–SDC4 engagement activated p38 phosphorylation, leading to transcriptional upregulation of the NLRP3 inflammasome and amplified inflammatory responses in chondrocytes. Conversely, SDC4 silencing mitigated MCs progression. Collectively, this study delineates a mechanism by which THBS1 ⁺ macrophages exacerbate lumbar endplate MCs through the SDC4–p38–NLRP3 axis. These findings provide a novel theoretical framework and highlight THBS1 and SDC4 as potential immunotherapeutic targets for modulating disc degeneration.