Interleukin‐34 Reprograms Glycolytic and Osteoclastic Rheumatoid Arthritis Macrophages via Syndecan 1 and Macrophage Colony‐Stimulating Factor Receptor

Objective In rheumatoid arthritis (RA), elevated serum interleukin‐34 (IL‐34) levels are linked with increased disease severity. IL‐34 binds to 2 receptors, macrophage colony‐stimulating factor receptor (M‐CSFR) and syndecan 1, which are coexpressed in RA macrophages. Expression of both IL‐34 and syndecan 1 is strikingly elevated in the RA synovium, yet their mechanisms of action remain undefined. This study was undertaken to investigate the mechanism of action of IL‐34 in RA. Methods To characterize the significance of IL‐34 in immunometabolism, its mechanism of action was elucidated in joint macrophages, fibroblasts, and T effector cells using RA and preclinical models. Results Intriguingly, syndecan 1 activated IL‐34–induced M‐CSFR phosphorylation and reprogrammed RA naive cells into distinctive CD14+CD86+GLUT1+ M34 macrophages that expressed elevated levels of IL‐1β, CXCL8, and CCL2. In murine M34 macrophages, the inflammatory phenotype was accompanied by potentiated glycolytic activity, exhibited by transcriptional up‐regulation of GLUT1, c‐Myc, and hypoxia‐inducible factor 1α (HIF‐1α) and amplified pyruvate and l ‐lactate secretion. Local expression of IL‐34 provoked arthritis by expanding the glycolytic F4/80‐positive, inducible nitric oxide synthase (iNOS)–positive macrophage population, which in turn attracted fibroblasts and polarized Th1/Th17 cells. The cross‐talk between murine M34 macrophages and Th1/Th17 cells broadened the inflammatory and metabolic phenotypes, resulting in the expansion of IL‐34 pathogenicity. Consequently, IL‐34–instigated joint inflammation was alleviated in RAG −/− mice compared to wild‐type mice. Syndecan 1 deficiency attenuated IL‐34–induced arthritis by interfering with joint glycolytic M34 macrophage and osteoclast remodeling. Similarly, inhibition of glycolysis by 2‐deoxy‐ d‐ glucose reversed the joint swelling and metabolic rewiring triggered by IL‐34 via HIF‐1α and c‐Myc induction. Conclusion IL‐34 is a novel endogenous factor that remodels hypermetabolic M34 macrophages and facilitates their cross‐regulation with T effector cells to advance inflammatory bone destruction in RA.