Eosinophil ETosis-mediated release of galectin-10 in eosinophilic granulomatosis with polyangiitis.

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. 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, asthmatics, and EGPA patients in active and remission states (n=15 per group) were examined. RESULTS EETosis was dependent on reactive oxygen species and peptidylarginine deiminase 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 into various tissues from EGPA patients. Serum eosinophil granule proteins and galectin-10 levels were increased in EGPA and positively correlated with disease activity assessed by Birmingham vasculitis activity score (galectin-10; r=0.8531, p<0.0001). When normalized by blood eosinophil count, 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 IL-5. 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 in patients with EGPA might reflect the systemic occurrence of cytolytic EETosis.