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Syntenin-1-mediated arthritogenicity is advanced by reprogramming RA metabolic macrophages and Th1 cells
  1. Anja Meyer1,2,
  2. Ryan E Sienes2,
  3. Wes Nijim2,
  4. Brian Zanotti3,
  5. Sadiq Umar1,2,
  6. Michael V Volin3,
  7. Katrien Van Raemdonck1,2,
  8. Myles Lewis4,5,
  9. Costantino Pitzalis6,
  10. Shiva Arami2,
  11. Mina Al-Awqati1,2,
  12. Huan J Chang1,2,
  13. Pim Jetanalin1,2,
  14. Georg Schett7,8,
  15. Nadera Sweiss2,
  16. Shiva Shahrara1,2
  1. 1Jesse Brown VA Medical Center, Chicago, Illinois, USA
  2. 2Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA
  3. 3Department of Microbiology and Immunology, Midwestern University, Downers Grove, Illinois, USA
  4. 4Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, UK
  5. 5Centre for Translational Bioinformatics, Queen Mary University of London William Harvey Research Institute, London, UK
  6. 6Experimental Medicine and Rheumatology, William Harvey Research Institute, London, UK
  7. 7Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
  8. 8Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
  1. Correspondence to Dr Shiva Shahrara, Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA; shahrara{at}


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
  • Inflammation
  • T-Lymphocyte subsets

Data availability statement

All data are available in the main text or online supplemental materials. RNAseq data are available under:

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Data availability statement

All data are available in the main text or online supplemental materials. RNAseq data are available under:

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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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.