The Multifaceted Roles of Macrophages in Rheumatoid Arthritis: From Cytokine Networks to the Discovery of Novel Subsets

Macrophages play a central and multifaceted role in the pathogenesis of rheumatoid arthritis (RA). This review synthesizes current understanding, emphasizing how M1/M2 polarization imbalance drives RA progression. Specifically, M1 promotes synovial inflammation, joint destruction, and pannus formation via pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and dysregulated angiogenesis. Conversely, functional impairment of anti-inflammatory M2 macrophages contributes to defective immune regulation. Beyond the classical M1/M2 dichotomy, macrophages exert their pathogenic influence through complex networks: activating adaptive immunity by phagocytosis and antigen presentation, secreting cytokines to regulate synovial tissue immune microenvironment and sustaining inflammation by metabolic reprogramming. Critically, heterogeneous macrophage subsets exhibit divergent roles. Recent studies have identified novel populations, such as pro-fibrotic SPP1+ macrophages and interferon-responsive STAT1+CXCL10+ macrophages. Future research may focus on reprogramming macrophage polarization, modulating metabolic pathways, targeting epigenetic regulators, or selectively manipulating specific pro-resolving subsets. The development of multi-target biologics, small molecules, and nanocarrier-based delivery systems could pave the way for personalized RA therapeutics.