Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
Ann Rheum Dis. 2021 Apr;80(4):451-468. doi: 10.1136/annrheumdis-2020-218902. Epub 2020 Nov 4.
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.
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.
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.
These findings point to a hitherto undiscovered proresolving signature in an eosinophil subset that stimulates arthritis resolution.
嗜酸性粒细胞在哮喘中具有促炎功能。然而，我们最近的研究表明，固有淋巴细胞 2 型（ILC2）和嗜酸性粒细胞在类风湿关节炎（RA）中有促缓解作用。目前尚不清楚决定嗜酸性粒细胞双重作用的机制。因此，我们研究了哮喘（一种典型的嗜酸性粒细胞疾病）是否可以引发慢性关节炎的缓解。
用卵清蛋白触发嗜酸性粒细胞性哮喘，同时用 K/BxN 血清诱导关节炎，通过单细胞 RNA 测序（scRNA-seq）比较肺部和滑膜中的嗜酸性粒细胞亚群。为了研究 ILC2-白细胞介素 5（IL-5）轴的参与，我们使用了白细胞介素 25（IL-25）和白细胞介素 33 质粒的流体动力学注射（HDI）、IL-5 报告小鼠和抗 IL-5 抗体治疗。在 RA 患者中，在外周血和滑膜组织中检查了不同的嗜酸性粒细胞亚群。在接受美泊利单抗（抗 IL-5 抗体）治疗之前和之后，监测了伴有哮喘的 RA 患者的疾病活动。
诱导嗜酸性粒细胞性哮喘导致了小鼠关节炎的缓解和关节组织的保护。scRNA-seq 显示，关节中有特定的调节性嗜酸性粒细胞（rEos）亚群，与肺部的炎症性嗜酸性粒细胞不同。从机制上讲，肺部 ILC2 释放的系统性上调的 IL-5 导致滑膜 rEos 扩增。嗜酸性粒细胞耗竭消除了哮喘对关节炎的有益作用。rEos 在缓解期的 RA 患者滑膜中持续存在，但在活动期则不存在。值得注意的是，在伴有哮喘的 RA 患者中，美泊利单抗治疗会引发关节炎的复发。
这些发现指出了一个以前未被发现的嗜酸性粒细胞亚群的促缓解特征，该特征刺激关节炎的缓解。
