IRF7 orchestrates proinflammatory macrophage polarization and joint destruction in rheumatoid arthritis.

objectivesRheumatoid 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.

methodsSingle-cell RNA sequencing (scRNA-seq) data and SCENIC analysis were used to identify TF-enriched macrophage subpopulations in the RA synovium. Chromatin immunoprecipitation sequencing data (ChIP-seq) were used to map IRF7 binding sites, and bulk RNA-seq data were used to analyse 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.

resultsA CD48highS100A12+ 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.

conclusionsIRF7 appears to promote pathogenic macrophage polarization and inflammatory signaling in RA, and its dysregulation has been associated with disease pathogenesis. Focal IRF7 perturbation can dampen pro-inflammatory networks, suggesting a potentially selective approach for tempering synovial inflammation while limiting systemic immunosuppression.