Eosinophils ETosis as a novel contributor to the pathogenesis of granulomatosis with polyangiitis

Granulomatosis with polyangiitis (GPA) is traditionally regarded as a neutrophil-driven necrotizing vasculitis. However, the potential involvement of eosinophilic inflammation has not been fully elucidated. We investigated the contribution of eosinophilic inflammation to the pathogenesis of GPA, with a particular focus on eosinophil extracellular trap formation (EETosis). This retrospective study included 52 patients, including 25 with active GPA and 27 in remission. We recorded enzyme-linked immunosorbent assay-based serum concentrations of eosinophil-derived proteins (galectin-10, eosinophil cationic protein, and eosinophil-derived neurotoxin), neutrophil-derived proteins (myeloperoxidase), and a marker for extracellular traps (citrullinated histone H3) for these patients. EETosis in tissue samples of patients was examined by immunofluorescence staining. Serum-induced EETosis was evaluated in vitro. Serum concentrations of galectin-10, eosinophil cationic protein, eosinophil-derived neurotoxin, citrullinated histone H3, and C-reactive protein and antineutrophil cytoplasmic antibody titre of patients with active GPA were significantly higher than those in remission. Galectin-10 had the strongest correlation with the Birmingham Vasculitis Activity Score (r = 0.778, P < 0.001). Increased galectin-10 levels were identified to be associated with the active stage after adjustment for glucocorticoid dose and eosinophil count. Receiver operating characteristic analyses of galectin-10 to discriminate between the active and remission phases revealed an area under the curve of 0.923, with 85.2% sensitivity and 91.1% specificity. GPA lung tissue showed lytic eosinophils and EETosis. Additionally, serum from active GPA patients induced EETosis in vitro whereas that from remission patients did not. Eosinophil activation and EETosis may contribute to the disease activity of GPA, highlighting a previously underrecognized component of its pathogenesis.