Eosinophils have functions in health and in the pathogeneses of asthma, allergies and other diseases. Some roles of eosinophils are based on their acute, effector responses, such as their capacity to release preformed granule contents, including their distinctive granule cationic proteins. Other eosinophil functions are based on their regulated expression of cell surface receptors and ligands and their release of diverse cytokines that can mediate interactions with other cells in the microenvironment of tissue sites. Eosinophils function principally in tissue sites, especially submucosal sites, where eosinophils localize even in the absence of disease. For tissue-resident eosinophils, definitions of the interactions that occur between eosinophils and other immune cells in tissue sites are germane to understanding eosinophil functions in acute and chronic diseases. Amongst leukocytes, the structure of eosinophils is highly unique. Eosinophils in tissue sites of inflammation, such as asthmatic airways, characteristically exhibit ultrastructural alterations indicative of distinct intracellular mechanisms governing their functional responses. Mechanisms of vesicular transport underlie a unique eosinophil """"""""degranulation"""""""" process that selectively releases only certain specific granule proteins; but these mechanisms have never been defined. Eosinophils are cellular sources of multiple cytokines which notably are stored preformed in intracellular sites, including specific granules; but mechanisms regulating such release of eosinophil-derived cytokines are unknown. Likewise, some relevant immunologic proteins, such as CD40, are abundantly present preformed in intracellular pools within eosinophils; but mechanisms underlying the regulated expression of such proteins have not been defined. Our studies will investigate aspects of the functioning of eosinophils that relate the unique structural cell biology of eosinophils to their distinct functional roles in immune homeostasis and pathology. We will investigate intracellular mechanisms involved in the regulated release and/or expression of eosinophil-derived proteins, including cytokines and cell-surface ligands/receptors. The overall hypothesis is that functional responses of eosinophils in immunologic and other diseases are dependent on intracellular compartmentalization of eosinophil proteins and governed by specific intracellular signaling and trafficking mechanisms that differentially regulate the expression of these eosinophil proteins. Understanding the molecular and cellular mechanisms that regulate the extracellular release of eosinophil granule-stored cytokines and expression of other proteins will provide novel insights into eosinophil functions that involve interactions between eosinophils and other cells in tissue sites.
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