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Secretion of inflammatory mediators from eosinophils and their tissue residing cell-free granules: mechanisms and implications in inflammation (eosinophil secretion)
Start date: Jan 1, 2015, End date: Dec 31, 2018 PROJECT  FINISHED 

Eosinophils, both as end-stage effector cells and as Th2-immunomodulators, have the capacity to secrete varied inflammatory mediators, such as, cytokines and enzymes that are stored in their cytoplasmic secretory granules. Among them are the cationic proteins: major basic protein, eosinophil peroxidase, and the eosinophil RNases. In the last decade several studies, both in vitro and in vivo, have revealed a pivotal role for eosinophils and their granule content in immunomodulation, host defence and in pathology of eosinophil-associated diseases, such as allergy and asthma. Eosinophil secretion of granules content (e.g. degranulation) and the deposit of its cationic proteins are associated with a range of inflammatory disorders. Degranulation typically by means of piecemeal degranulation, is a controlled and selective process. In addition, at sites of inflammation, cytolysed eosinophils release cell-free granules, that reside in inflamed tissue.Recently, studies by me and my colleagues have revealed that beside secretion from intact cells, cell-free granules released from human and mouse eosinophils during lysis have the ability to secrete their content in response to cytokine stimulation in a cell free context. However, the mechanisms of these two methods of secretion and the key factors that participate in the degranulation process in intact eosinophils and especially in cell-free granules are poorly understood.The current proposal aims to explore the physiological functions of the newly discovered mode of secretion from eosinophil-derived cell free granules in allergic airway inflammation and the mechanisms by which integrins cooperate with elements of the cytoskeleton machinery in regulating chemokine-mediated degranulation in eosinophils. These studies will enhance our understanding of eosinophil degranulation, on the molecular and pathopysiological levels, and will provide potential targets for new directed therapies to treat eosinophil-associated diseases.
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