The many facets of macrophages in rheumatoid arthritis

Macrophages are central to the pathophysiology of rheumatoid arthritis (RA). They constitute the main source of pro-inflammatory cytokines and chemokines such as TNF and IL-1β, they activate a wide range of immune and non-immune cells, and they secrete diverse tissue degrading enzymes driving chronic pro-inflammatory, tissue destructive and pain responses in RA. However, they can also produce anti-inflammatory cytokines such as IL-10, secrete inhibitors of tissue degrading enzymes and promote immunoregulatory and protective responses, suggesting the existence of macrophages with distinct and diverse functional activities. Although the underlying basis of this phenomenon has remained obscure for years, emerging evidence has now provided insight into the mechanisms and molecular processes involved. Here, we review current knowledge on the biology of macrophages in RA, and highlight recent literature on the heterogeneity, origins and ontogeny of macrophages as part of the mononuclear phagocyte system. We also discuss their plasticity in the context of the M1/M2 paradigm, and the emerging theme of metabolic rewiring as a major mechanism for programming macrophage functions and pro-inflammatory activities. This sheds light into the many facets of macrophages in RA, their molecular regulation and their translational potential for developing novel protective and therapeutic strategies in the clinic.