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Cytokine-directed cellular cross-talk imprints synovial pathotypes in rheumatoid arthritis
  1. Maximilian Kugler1,
  2. Mirjam Dellinger1,2,
  3. Felix Kartnig1,3,
  4. Lena Müller1,4,
  5. Teresa Preglej1,
  6. Leonhard X Heinz1,
  7. Elisabeth Simader1,
  8. Lisa Göschl1,
  9. Stephan E Puchner5,
  10. Sebastian Weiss6,
  11. Lisa E Shaw7,
  12. Matthias Farlik7,
  13. Wolfgang Weninger7,
  14. Giulio Superti-Furga3,8,
  15. Josef S Smolen1,
  16. Guenter Steiner1,2,
  17. Daniel Aletaha1,
  18. Hans P Kiener1,
  19. Myles J Lewis9,10,
  20. Costantino Pitzalis9,11,
  21. Anela Tosevska1,
  22. Thomas Karonitsch1,
  23. Michael Bonelli1,2
  1. 1 Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
  2. 2 Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Vienna, Austria
  3. 3 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
  4. 4 Core Facility Flow Cytometry, Medical University of Vienna, Vienna, Austria
  5. 5 Department of Orthopaedic Surgery, Medical University of Vienna, Vienna, Austria
  6. 6 Department of Pathology, Medical University of Vienna, Vienna, Austria
  7. 7 Department of Dermatology, Medical University of Vienna, Vienna, Austria
  8. 8 Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
  9. 9 Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University and The London School of Medicine and Dentistry, London, UK
  10. 10 Centre for Translational Bioinformatics, William Harvey Research Institute, Queen Mary University and The London School of Medicine and Dentistry, London, UK
  11. 11 Department of Biomedical Sciences, Humanitas University & IRCCS Humanitas Research Hospital, Milan, Italy
  1. Correspondence to Dr Michael Bonelli, Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna A-1090, Austria; michael.bonelli{at}meduniwien.ac.at; Dr Anela Tosevska; anela.tosevska{at}meduniwien.ac.at; Dr Thomas Karonitsch; thomas.karonitsch{at}meduniwien.ac.at

Abstract

Introduction Structural reorganisation of the synovium with expansion of fibroblast-like synoviocytes (FLS) and influx of immune cells is a hallmark of rheumatoid arthritis (RA). Activated FLS are increasingly recognised as a critical component driving synovial tissue remodelling by interacting with immune cells resulting in distinct synovial pathotypes of RA.

Methods Automated high-content fluorescence microscopy of co-cultured cytokine-activated FLS and autologous peripheral CD4+ T cells from patients with RA was established to quantify cell–cell interactions. Phenotypic profiling of cytokine-treated FLS and co-cultured T cells was done by flow cytometry and RNA-Seq, which were integrated with publicly available transcriptomic data from patients with different histological synovial pathotypes. Computational prediction and knock-down experiments were performed in FLS to identify adhesion molecules for cell–cell interaction.

Results Cytokine stimulation, especially with TNF-α, led to enhanced FLS-T cell interaction resulting in cell-cell contact-dependent activation, proliferation and differentiation of T cells. Signatures of cytokine-activated FLS were significantly enriched in RA synovial tissues defined as lymphoid-rich or leucocyte-rich pathotypes, with the most prominent effects for TNF-α. FLS cytokine signatures correlated with the number of infiltrating CD4+ T cells in synovial tissue of patients with RA. Ligand-receptor pair interaction analysis identified ICAM1 on FLS as an important mediator in TNF-mediated FLS-T cell interaction. Both, ICAM1 and its receptors were overexpressed in TNF-treated FLS and co-cultured T cells. Knock-down of ICAM1 in FLS resulted in reduced TNF-mediated FLS-T cell interaction.

Conclusion Our study highlights the role of cytokine-activated FLS in orchestrating inflammation-associated synovial pathotypes providing novel insights into disease mechanisms of RA.

  • Rheumatoid Arthritis
  • Inflammation
  • Fibroblasts
  • Cytokines
  • T-Lymphocyte subsets

Data availability statement

Data are available on reasonable request. RNA-Seq data are available upon request. Please contact anela.tosevska@meduniwien.ac.at

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Data availability statement

Data are available on reasonable request. RNA-Seq data are available upon request. Please contact anela.tosevska@meduniwien.ac.at

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Footnotes

  • MK and MD are joint first authors.

  • AT, TK and MB are joint senior authors.

  • Handling editor David S Pisetsky

  • MK and MD contributed equally.

  • AT, TK and MB contributed equally.

  • Contributors All authors contributed to manuscript preparation. MK, MD, AT, FK, LM, LXH, TP, ES, LG, SW, HPK, TK and MB contributed to experimental design of the study. MK, AT and MD contributed to data analysis. MK and MD performed cellular assays. MK, AT, TK and MB drafted the primary manuscript. SEP, TK and MB contributed to patient recruitment. CP, MJL, LES, MF and WW contributed to the revision of this study. GS-F, JSS, DA, GS, CP and MJL provided expertise and contributed to manuscript finalisation. MK and MD contributed equally as co-first authors in the revised manuscript. AT, TK and MB contributed equally and are co-last authors. MB is responsible for the overall content as the guarantor of this manuscript.

  • Competing interests MB reports about personal fees from Eli-Lilly and received grants from Galapagos, DA received grants and consulting fees from AbbVie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche and Sandoz

    and is an editorial board member of Annals of the Rheumatic Diseases, JSS reports about grants, consulting and personal fees from AbbVie, Astra-Zeneca, Lilly, Novartis, Amgen, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung and UCB and is editor-in-chief of Annals of the Rheumatic Diseases. ES reports speaker fees from Eli-Lilly and supports for attendance of meetings from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim and Astra Zeneca. CP and is an editorial board member of Annals of the Rheumatic Diseases. The authors CP and MJL are named inventors on a patent application (no. GB 2100821.4), submitted by Queen Mary University of London, that covers methods used to select treatments in rheumatoid arthritis. All other authors declare no competing interests.

  • 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.

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