Eosinophil ETosis–Mediated Release of Galectin‐10 in Eosinophilic Granulomatosis With Polyangiitis

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 73; no. 9; pp. 1683 - 1693
• Main Authors: Fukuchi, Mineyo, Kamide, Yosuke, Ueki, Shigeharu, Miyabe, Yui, Konno, Yasunori, Oka, Nobuyuki, Takeuchi, Hiroki, Koyota, Souichi, Hirokawa, Makoto, Yamada, Takechiyo, Melo, Rossana C. N., Weller, Peter F., Taniguchi, Masami
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2021
• Subjects: Asthma; Bioaccumulation; Blood; Cell death; Cell fate; Churg-Strauss syndrome; Citrulline; Correlation; Disease; Electron microscopy; Eosinophils; Granular materials; Granulomatosis; Histones; Immune system; In vitro methods and tests; Inflammatory diseases; Interleukins; Leukocytes (eosinophilic); Protein-arginine deiminase; Proteins; Reactive oxygen species; Remission; Tissues; Vasculitis; Vein & artery diseases; galectin-10; eosinophils; extracellular traps; eosinophilic granulomatosis with polyangiitis; ETosis
• ISSN: 2326-5191; 2326-5205
• DOI: 10.1002/art.41727

Objective Eosinophils are tissue‐dwelling immune cells. Accumulating evidence indicates that a type of cell death termed ETosis is an important cell fate involved in the pathophysiology of inflammatory diseases. Although the critical role of eosinophils in eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg‐Strauss syndrome) is well established, the presence of eosinophil ETosis (EETosis) is poorly understood. We undertook this study to better understand the characteristics of EETosis. Methods In vitro studies using blood‐derived eosinophils were conducted to characterize EETosis. The occurrence of EETosis in tissues from patients with EGPA was studied by immunostaining and electron microscopy. Serum concentrations of eosinophil‐derived proteins in healthy controls, patients with asthma, and EGPA patients with active disease or with disease in remission (n = 15 per group) were examined. Results EETosis was reliant on reactive oxygen species and peptidylarginine deiminase type 4–dependent histone citrullination, resulting in the cytolytic release of net‐like eosinophil extracellular traps, free galectin‐10, and membrane‐bound intact granules. The signature of EETosis, including loss of cytoplasmic galectin‐10 and deposition of granules, was observed in eosinophils infiltrating various tissues from EGPA patients. Serum eosinophil granule proteins and galectin‐10 levels were increased in EGPA and positively correlated with disease activity as assessed by the Birmingham Vasculitis Activity Score (r = 0.8531, P < 0.0001 for galectin‐10). When normalized to blood eosinophil counts, this correlation remained for galectin‐10 (r = 0.7168, P < 0.0001) but not for granule proteins. Galectin‐10 levels in active EGPA positively correlated with serum interleukin‐5 levels. Conclusion Eosinophils infiltrating diseased tissues in EGPA undergo EETosis. Considering the exclusive expression and large pool of cytoplasmic galectin‐10 in eosinophils, elevated serum galectin‐10 levels in patients with EGPA might reflect the systemic occurrence of cytolytic EETosis.