IL-34 reprograms glycolytic and osteoclastic RA macrophages via Syndecan-1 and M-CSFR

OBJECTIVE: In RA, IL-34 serum levels are linked with increased disease severity. IL-34 binds to two receptors, M-CSFR and Syndecan-1 (SDC-1), which are co-expressed in RA macrophages (MФs). Expression of both IL-34 and SDC-1 is strikingly elevated in the RA synovium, yet their mechanism of action remains undefined. METHODS: To characterize the significance of IL-34 in immunometabolism, its mechanism of action was elucidated in joint MФs, fibroblasts and effector T cells using RA and preclinical models. RESULTS: Intriguingly, SDC-1 activates IL-34-induced M-CSFR phosphorylation and reprograms RA naïve cells into distinctive CD14(+)CD86(+)GLUT1(+)M34 MФs that express elevated levels of IL-1β, CXCL8 and CCL2. In murine M34 MФs, the inflammatory phenotype is accompanied by potentiated glycolytic activity, exhibited by transcriptional upregulation of GLUT1, C-MYC and HIF1α and amplified pyruvate and L-lactate secretion. Local expression of IL-34 provokes arthritis, by expanding the glycolytic F4/80(+)iNOS(+)MΦ population, which in turn attracts fibroblasts and polarizes Th1/Th17 cells. The crosstalk between murine M34 MΦs and Th1/Th17 cells broadens the inflammatory and metabolic phenotypes resulting in the expansion of IL-34 pathogenicity. Consequently, IL-34-instigated joint inflammation was alleviated in RAG−/− compared to wild type mice. Consistently, SDC-1 deficiency attenuated IL-34-induced arthritis by interfering with joint glycolytic M34 MΦ and osteoclast remodeling. Similarly, inhibition of glycolysis by 2-DG reversed the joint swelling and metabolic rewiring triggered by IL-34 via HIF1α and C-MYC induction. CONCLUSION: IL-34 is a novel endogenous factor that remodels hypermetabolic M34 MΦs and facilitates their cross-regulation with effector T cells to advance RA inflammatory bone destruction.