Objectives Syntenin-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.
Methods RA 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.
Results Syntenin-1 and syndecan-1 (SDC-1) co-localise on RA ST macrophages (MΦs) 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+MΦs 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 MΦs-reprogrammed by syntenin-1. In syntenin-1-induced arthritis, F4/80+iNOS+RAPTOR+MΦs represent glycolytic RA MΦs, 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 MΦ 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.
Conclusion The syntenin-1/SDC-1 pathway plays a critical role in the inflammatory and metabolic landscape of RA through glycolytic MΦ and Th1 cell cross-regulation (graphical abstract).
- Arthritis, Rheumatoid
- T-Lymphocyte subsets
Data availability statement
All data are available in the main text or online supplemental materials. RNAseq data are available under: https://peac.hpc.qmul.ac.uk/.
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Handling editor Josef S Smolen
Contributors Conceptualisation: AM, SS. Methodology: AM, RES, WN, BZ, MVV, ML, CP and SS. Investigation: AM, RES, WN, BZ, SU, MVV, KVR, ML, CP, SA, MA-A, HJC, PJ, NS and SS. Visualisation: AM, BZ, MVV and SS. Funding acquisition: SS. Project administration: AM, SS. Supervision: AM and SS. Writing-original draft: AM, SS. Writing-review and editing: AM, RES, WN, BZ, SU, MVV, KVR, ML, CP, SA, MA-A, HJC, PJ, GS, NS and SS. Guarantor: SS.
Funding This work was supported in part by awards from the Department of Veteran’s Affairs MERIT Award BX002286, the National Institutes of Health NIH R01 AI167155, NIH R41 AI147697, the Innovative Research Award from the Rheumatology Research Foundation (RRF).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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