Syntenin-1-mediated arthritogenicity is advanced by reprogramming RA metabolic macrophages and Th1 cells

ObjectivesSyntenin-1, a novel endogenous ligand, was discovered to be enriched in rheumatoid arthritis (RA) specimens compared with osteoarthritis synovial fluid and normal synovial tissue (ST). However, the cellular origin, immunoregulation and molecular mechanism of syntenin-1 are undescribed in RA. MethodsRA patient myeloid and lymphoid cells, as well as preclinical models, were used to investigate the impact of syntenin-1/syndecan-1 on the inflammatory and metabolic landscape. ResultsSyntenin-1 and syndecan-1 (SDC-1) co-localise on RA ST macrophages (M phi s) and endothelial cells. Intriguingly, blood syntenin-1 and ST SDC-1 transcriptome are linked to cyclic citrullinated peptide, erythrocyte sedimentation rate, ST thickness and bone erosion. Metabolic CD14(+)CD86(+)GLUT1(+)M phi s reprogrammed by syntenin-1 exhibit a wide range of proinflammatory interferon transcription factors, monokines and glycolytic factors, along with reduced oxidative intermediates that are downregulated by blockade of SDC-1, glucose uptake and/or mTOR signalling. Inversely, IL-5R and PDZ1 inhibition are ineffective on RA M phi s-reprogrammed by syntenin-1. In syntenin-1-induced arthritis, F4/80(+)iNOS(+)RAPTOR(+)M phi s represent glycolytic RA M phi s, by amplifying the inflammatory and glycolytic networks. Those networks are abrogated in SDC-1(-/-) animals, while joint prorepair monokines are unaffected and the oxidative metabolites are moderately replenished. In RA cells and/or preclinical model, syntenin-1-induced arthritogenicity is dependent on mTOR-activated M phi remodelling and its ability to cross-regulate Th1 cells via IL-12 and IL-18 induction. Moreover, RA and joint myeloid cells exposed to Syntenin-1 are primed to transform into osteoclasts via SDC-1 ligation and RANK, CTSK and NFATc1 transcriptional upregulation. ConclusionThe syntenin-1/SDC-1 pathway plays a critical role in the inflammatory and metabolic landscape of RA through glycolytic M phi and Th1 cell cross-regulation (graphical abstract).

Automated summary

The study found that syntenin-1 is enriched in rheumatoid arthritis (RA) specimens compared to osteoarthritis synovial fluid and normal synovial tissue. However, the cellular origin, immunoregulation and molecular mechanism of syntenin-1 in RA are still unknown.