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Regulatory eosinophils induce the resolution of experimental arthritis and appear in remission state of human rheumatoid arthritis
  1. Darja Andreev1,
  2. Mengdan Liu1,
  3. Katerina Kachler1,
  4. Mireia Llerins Perez1,
  5. Philipp Kirchner2,
  6. Julia Kölle3,
  7. Andreas Gießl4,
  8. Simon Rauber1,
  9. Rui Song1,
  10. Oliver Aust1,
  11. Anika Grüneboom1,
  12. Arnd Kleyer1,
  13. Juan D Cañete5,
  14. Arif Ekici2,
  15. Andreas Ramming1,
  16. Susetta Finotto3,
  17. Georg Schett1,
  18. Aline Bozec1
  1. 1 Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
  2. 2 Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
  3. 3 Department of Molecular Pneumology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
  4. 4 Department of Ophthalmology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
  5. 5 Departamento de Reumatología, Hospital Clínic de Barcelona e IDIBAPS, Barcelona, Spain
  1. Correspondence to Professor Aline Bozec, Department of Internal Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen 91054, Germany; aline.bozec{at}uk-erlangen.de

Abstract

Objectives Eosinophils possess pro-inflammatory functions in asthma. However, our recent studies have suggested that innate lymphoid cells type 2 (ILC2s) and eosinophils have proresolving properties in rheumatoid arthritis (RA). Nothing is known yet about the mechanisms determining the double-edged role of eosinophils. Therefore, we investigated whether asthma, a paradigm eosinophilic disease, can elicit resolution of chronic arthritis.

Methods Ovalbumin-triggered eosinophilic asthma was combined with K/BxN serum-induced arthritis, where lung and synovial eosinophil subsets were compared by single-cell RNA sequencing (scRNA-seq). To investigate the involvement of the ILC2–interleukin-5 (IL-5) axis, hydrodynamic injection (HDI) of IL-25 and IL-33 plasmids, IL-5 reporter mice and anti-IL-5 antibody treatment were used. In patients with RA, the presence of distinct eosinophil subsets was examined in peripheral blood and synovial tissue. Disease activity of patients with RA with concomitant asthma was monitored before and after mepolizumab (anti-IL-5 antibody) therapy.

Results The induction of eosinophilic asthma caused resolution of murine arthritis and joint tissue protection. ScRNA-seq revealed a specific subset of regulatory eosinophils (rEos) in the joints, distinct from inflammatory eosinophils in the lungs. Mechanistically, synovial rEos expanded on systemic upregulation of IL-5 released by lung ILC2s. Eosinophil depletion abolished the beneficial effect of asthma on arthritis. rEos were consistently present in the synovium of patients with RA in remission, but not in active stage. Remarkably, in patients with RA with concomitant asthma, mepolizumab treatment induced relapse of arthritis.

Conclusion These findings point to a hitherto undiscovered proresolving signature in an eosinophil subset that stimulates arthritis resolution.

  • arthritis
  • rheumatoid
  • inflammation
  • immune system diseases
  • cytokines
  • autoimmune diseases

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Footnotes

  • Handling editor Josef S Smolen

  • DA and ML contributed equally.

  • Presented at A part of this work was previously presented at EULAR Congress 2020 (DOI: 10.1136/annrheumdis-2020-eular.4479).

  • Funding This study was supported by the Collaborative Research Centre 1181 project-A01, the German Research Foundation BO-3811/5–1; BO-3811/6–1; FOR2886 TP02; the SPP μBone, the Interdisciplinary Center for Clinical Research grant A77 and J76, and the European Research Council Synergy Grant 4D Nanoscope.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval All mouse experiments were performed according to the rules and regulations of the animal facility Franz-Penzoldt-Zentrum, Erlangen and approved by the animal ethical committee of the government of Unterfranken, Würzburg, Germany. All analyses of human material were performed in accordance with the institutional guidelines and with the approval of the ethics committee of the Universitätsklinikum Erlangen and the Hospital Clinic of Barcelona, and signed declaration of consent was obtained from each patient.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All sequencing data have been deposited in the National Centre for Biotechnology Information Gene Expression Omnibus (GEO). The accession number for the sequencing data reported in this paper is GEO: GSE153632. All other relevant data and scripts are available on request.

  • 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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