Eosinophil granules function extracellularly as receptor-mediated secretory organelles

Abstract

Intracellular granules in several types of leukocytes contain preformed proteins whose secretions contribute to immune and inflammatory functions of leukocytes, including eosinophils, cells notably associated with asthma, allergic inflammation, and helminthic infections. Cytokines and chemokines typically elicit extracellular secretion of granule proteins by engaging receptors expressed externally on the plasma membranes of cells, including eosinophils. Eosinophil granules, in addition to being intracellular organelles, are found as intact membrane-bound structures extracellularly in tissue sites of eosinophil-associated diseases. Neither the secretory capacities of cell-free eosinophil granules nor the presence of functional cytokine and chemokine receptors on membranes of leukocyte granules have been recognized. Here, we show that granules of human eosinophils express membrane receptors for a cytokine, IFN-␥, and G protein-coupled membrane receptors for a chemokine, eotaxin, and that these receptors function by activating signal-transducing pathways within granules to elicit secretion from within granules. Capacities of intracellular granule organelles to function autonomously outside of eosinophils as independent, ligand-responsive, secretion-competent structures constitute a novel postcytolytic mechanism for regulated secretion of eosinophil granule proteins that may contribute to eosinophil-mediated inflammation and immunomodulation.allergy ͉ specific ͉ eotaxin ͉ IFN-␥

Eosinophil extracellular DNA trap cell death mediates lytic release of free secretion-competent eosinophil granules in humans

“…11,12 Cell-free human and mouse eosinophil granules with receptor-mediated activation of intragranule signaling pathways can directly secrete selected granule-derived proteins, including ECP, EPO, ribonucleases, and cytokines, for example, the interleukins IL-4 and IL-6. [12][13][14] Thus, the local tissue release of cell-free, secretion-competent eosinophil granules, secondary to eosinophil lysis, might constitute a means by which postmortem eosinophils could continue to provide immunoregulatory, pro-inflammatory, and other immunopathogenic stimuli. Despite these observations, the mechanisms of the eosinophil cytolytic release of their intact granules are not well known.…”

Cyclophilin D regulates necrosis, but not apoptosis, of murine eosinophils

“…Recent in vitro studies demonstrated primary eosinophil lysis after stimulation by a Ca 2ϩ ionophore or Siglec-8 engagement on primed human eosinophils (18,38). In addition, these cell-free eosinophil granules can directly secrete their constituents, including eosinophil cationic protein, EPX, ribonucleases, and cytokines, via cytokines, chemokines, and eicosanoids ligating to a granule's membrane-bound receptors (24,25,31). Thus it is tempting to speculate that the released cell-free, secretion-competent eosinophil granules could continue to provide proinflammatory, immunoregulatory, and other immunopathogenic stimuli secondary to the primary eosinophil lysis.…”

SIRPα/CD172a Regulates Eosinophil Homeostasis

“…However, extensive eosinophil degranulation and pulmonary pathologies could be induced in double-transgenic mice expressing IL-5 and eotaxin-2 coordinately by mature T cells and lung epithelial cells, respectively (47), implying that in vivo eosinophil effector functions mediated by degranulation might involve multiple costimulatory receptor-ligand interactions. In addition, previous studies in man indicated that eosinophil granules are secreted extracellularly as intact membrane-bound structures and that external stimulation is required to elicit secretion from the granules (14,48). The small intestine may lack the endogenous activating signal necessary for the ejection of toxic granular contents from the released MBP + CD63 + granules, preventing any obvious tissue damage.…”