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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.
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