IRF7 orchestrates proinflammatory macrophage polarization and joint destruction in rheumatoid arthritis

Objectives Rheumatoid arthritis (RA) involves synovial inflammation driven by pathogenic macrophages, whose polarization is regulated by transcription factors (TFs). Interferon regulatory factor 7 (IRF7) is an innate immune regulator, but its role in RA macrophage-mediated inflammation and cartilage destruction remains unclear. This study aimed to define IRF7-dependent regulatory pathways in RA macrophages and evaluate their therapeutic potential. Methods Single-cell RNA sequencing (scRNA-seq) data and SCENIC analysis were used to identify TF-enriched macrophage subpopulations in the RA synovium. Chromatin immunoprecipitation sequencing (ChIP-seq) was used to map IRF7 binding sites, and bulk RNA-seq was used to analyze M1 polarization responses. Functional validation included IRF7 knockdown in human monocytes and intra-articular siRNA in a collagen-induced arthritis (CIA) mouse model to assess inflammatory genes, macrophage polarization, and joint pathology. Results A CD48 ^high S100A12 ⁺ proinflammatory macrophage subset was expanded in RA and enriched for IRF7 activity and downstream genes (PTGS2, CXCL10, NF-κB1, and IL-1β). IRF7 directly regulates these genes, and its knockdown reduces M1 polarization and inflammatory gene expression in vitro. In CIA mice, local IRF7 silencing attenuated joint inflammation, synovial hyperplasia, and bone erosion, which correlated with decreased proinflammatory macrophages and increased regulatory T cells. Conclusions IRF7 drives pathogenic macrophage polarization and inflammatory signaling in RA, linking its dysregulation to disease pathogenesis. Local targeting of IRF7 disrupts proinflammatory networks, suggesting a precise strategy to mitigate synovial inflammation without systemic immunosuppression.