Contemporary understanding of the secretory granules in human eosinophils

Abstract

Eosinophil secretory (specific) granules have a unique morphology and are both a morphologic hallmark of eosinophils and fundamental to eosinophil-mediated responses. Eosinophil mediators with multiple functional activities are presynthesized and stored within these granules, poised for very rapid, stimulus-induced secretion. The structural organization and changes of eosinophil specific granules are revealing in demonstrating the complex and diverse secretory activities of this cell. Here, we review our current knowledge on the architecture, composition, and function of eosinophil specific granules as highly elaborated organelles able to produce vesiculotubular carriers and to interplay with the intracellular vesicular trafficking. We reconsider prior identifications of eosinophil cytoplasmic granules, including "primary," "secondary," "microgranules," and "small granules"; and consonant with advances, we provide a contemporary recognition that human eosinophils contain a single population of specific granules and their developmental precursors and derived secretory vesicles.

Keywords: Eosinophil Sombrero Vesicles; cell secretion; degranulation; immune responses; inflammation; transmission electron microscopy; vesicular trafficking.

Figure 1. Developmental morphology of specific granules within human eosinophils

Cored granules of mature human eosinophils are of a single type derived by transition from spherical coreless granules. During maturation in the bone marrow, immature specific granules undergo condensation and crystallization of their cores. (1) Immature granule in process of condensation showing intragranular vesicles surrounding the dense granule content; (2) Round immature granule with homogenously dense content; (3) Spherical core-containing granule seen with an electron-dense central area surrounded by an less dense region; (4) Resting, elliptical granule with a well-defined electron-dense core and an electron-lucent matrix; (5) An activated granule shows disassembling of its core and matrix and formation of vesiculotubular structures (EoSVs). All granules are delimited by a phospholipid bilayer membrane. A mixture of granules (1), (2) and (3) is observed in precursor cells (eosinophilic myelocytes) of the eosinophil lineage. The density of these granules is variable. Initially, small numbers of granule (3) are interspersed among large numbers of coreless granules (1) and (2) [34, 85]. Granules (4) and (5) are typical of mature eosinophils from the peripheral blood and tissues [5, 74].

Figure 2. Ultrastructure of eosinophil specific granules in humans

(A) A representative resting eosinophil show the cytoplasm packed with granules full of contents with typical morphology. Each granule has a central electron-dense core surrounded by an electron-lucent matrix and a delimiting membrane. (B and C) Degranulating eosinophils show morphological pattern of compound exocytosis (B), characterized by large channels formed by granule-granule fusions and wholesale release of granule contents, and piecemeal degranulation (PMD) (C), characterized by progressive emptying of the secretory granules in the absence of granule fusions and specific release of granule contents. Granule enlargement, disarrangement of the cores and matrices and increased formation of EoSVs (highlighted in pink) are observed during PMD. The boxed areas in (A–C) are shown in high magnification in (Ai-Ci). Eosinophils were isolated from the peripheral blood by negative selection, stimulated for one hour with TNF-α (B) or CCL11 (C), immediately fixed and processed for conventional TEM. N, nucleus; Gr, specific granules; LB, lipid body. Scale bars, 900 nm (A, C); 1.0 μm (B); 600 nm (Ai, Bi); 500 nm (Ci).