Human Eosinophils: Mechanisms of Functioning

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DESCRIPTION (provided by applicant): Eosinophils, cells of the innate immune system, have functions in health and in the pathogeneses of asthma, allergies and other diseases. While some functions of eosinophils are based on their acute, effector responses to release preformed granule cationic proteins, other eosinophil functions are based on their regulated release of diverse cytokines that can mediate interactions with other cells in the microenvironment of tissue sites. Eosinophils function in tissues, especially submucosal sites where eosinophils localize even in the absence of disease. Defining eosinophil cytokine-mediated functional interactions between eosinophils and other cells in tissues is germane to understanding eosinophil functions in both ongoing immune homeostasis and acute and chronic diseases. Amongst leukocytes, eosinophils distinctly contain multiple preformed cytokines stored within morphologically unique granules and secretory vesicles. Eosinophils in tissue sites of inflammation, such as asthmatic airways, exhibit ultrastructural alterations indicative of a specific "piecemeal degranulation" process based on vesicular transport, not exocytosis, that releases, with selectivity, specific proteins from eosinophil granules. In contrast to lymphocytes, cells of the adaptive immune system, a special capacity of eosinophils is their potential to rapidly release preformed cytokines; but mechanisms regulating selective release of eosinophil-derived cytokines remain to be delineated. Studies will investigate mechanisms involved in the regulated release of eosinophil-derived proteins, including cytokines. The overall hypothesis is that, central to the functions of eosinophils, the intracellular compartmentalization, trafficking and release of relevant eosinophil proteins, including cytokines, are dependent on regulatory mechanisms that with stimulus dependent specificity can finely regulate the differential and selective secretion of cytokines. Aims are to define: 1) eosinophil vesicle and granule mechanisms involved in cytokine release; 2) intracellular mechanisms for specificity of eosinophil cytokine release; and 3) stimulus-dependent mobilization and release of eosinophil cytokines. Understanding molecular and cellular mechanisms that regulate the extracellular release of eosinophil-derived cytokines will provide insights into eosinophil functions that involve interactions between eosinophils and other cells in tissue sites in the lung and elsewhere and may identify new therapeutic approaches.