Degranulation in macrophages and other leukocytes: regulation by calcium, phosphoinositide 3-kinase, and protein kinase C

Abstract: Macrophages mediate innate immunity through release of cytokines, eicosanoids, reactive oxygen species as well as through phagocytosis and secretion of lysosomal enzymes. Regulation of lysosomal secretion in macrophages differs in several respects from release of specialized granules in other leukocytes. Lysosomal secretion is not dependent upon cytosolic calcium but is instead triggered by lysosomal alkalinization and is modulated by cytosolic pH. Common to secretory responses in most leukocytes, on the other hand, is a regulation by protein kinase C. Immune complexes trigger a localized azurophilic degranulation in neutrophils which is dependent upon protein kinase C. An enrichement of conventional isoforms at the target area of the plasma membrane further implies a role for these kinases in the spatial regulation of degranulation. Lysosomal secretion in macrophages is likewise regulated by protein kinase C. This regulation is also exerted by conventional isoforms but involves both enhancing and repressing signaling pathways. Activation of protein kinase C reduces secretion through inhibition of lysosomal alkalinization while at the same time inducing a compensatory enhancement downstream of the lysosomal alkalinization. Both pathways are sensitive to depletion of cytosolic calcium and are blocked by down-regulation of conventional isoforms of protein kinase C. The pathway acting on lysosomal pH involves signaling through phosphoinositide 3-kinase. Inhibition of this kinase abrogates translocation of conventional isoforms of protein kinase C to lysosomes.