Mechanistic role of eosinophils in the initiation and progression of pancreatitis pathogenesis

Abstract

Abstract Several clinical reports indicated that IL-18 and eosinophils are induced in patient with chronic pancreatitis and pancreatic malignancy. However, the etiology and pathogenesis of eosinophilic pancreatitis (EP) is poorly understood and termed as rare disease. Accordingly, we tested the hypothesis that IL-18 and IL-5 synergy may be critical in promoting EP pathogenesis. We performed qPCR, ELISA, western blot, immunofluorescence and immunohistochemical analyses to detect eosinophils, mast cells, collagen, associated cytokines and chemokines in experimental and human pancreatitis. Herein, we show the evidence of tissue eosinophilic microabscesses, mast cells and collagen accumulation in non-malignant and malignant human pancreatitis. Additionally, we observed more prominent collagen accumulation, fibrotic lesions and degranulated eosinophils in malignant pancreatic tissue samples compare to non-malignant pancreatic samples. A similar characteristics such as acinar cells atrophy, increased accumulation of tissue eosinophils, mast cells and induced levels of IL-5, IL-18, Eotaxin-2, TGF-β1, Collagen-1, Collagen-3, fibronectin and α-SMA was observed in cerulein-induced chronic mouse model of pancreatitis. Mechanistically, we show that IL-5 deficiency in mice protect pancreatic pathogenesis including fibrosis in cerulein-induced mouse model of pancreatitis, indicating a critical role of eosinophils in disease pathogenesis. Taken together, our combined clinical and experimental data indicates that eosinophils accumulation and degranulation may be critical in promoting pancreatic fibrosis that may leads to pancreatic malignancy.