Single-Cell RNA Sequencing Reveals Heterogeneity of Synovial Macrophages and Identifies Novel Inflammatory Subpopulations in Rheumatoid Arthritis Patients

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovial inflammation and joint destruction. Synovial macrophages play a pivotal role in the pathogenesis of RA, yet their phenotypic heterogeneity and distinct functional roles remain incompletely understood. In this study, we utilized single-cell RNA sequencing (scRNA-seq) to profile 18,432 individual cells from the synovial tissue of patients with active RA (n=6) and osteoarthritis controls (n=4). Unbiased clustering analysis identified five distinct synovial macrophage subpopulations, including a novel proinflammatory subpopulation characterized by high expression of CXCL8, IL1B, and TREM1 (designated as TREM1^high inflammatory macrophages). This subpopulation exhibited a highly active metabolic state with upregulated glycolysis and oxidative phosphorylation pathways. Ligand-receptor interaction analysis revealed that TREM1^high macrophages communicate extensively with synovial fibroblasts and T cells via the CCL3/CCL4-CCR5 and CXCL8-CXCR1/2 axes, driving the recruitment and activation of other immune cells. Furthermore, spatial transcriptomics validated the localization of these inflammatory macrophages within the sublining zone of the inflamed synovium. Our findings resolve the cellular landscape of synovial macrophages in RA, identifying a novel TREM1^high inflammatory subpopulation as a potential therapeutic target for mitigating synovial inflammation and joint damage.