Functions of tissue-resident eosinophils - PubMed (original) (raw)
Review
. 2017 Dec;17(12):746-760.
doi: 10.1038/nri.2017.95. Epub 2017 Sep 11.
Affiliations
- PMID: 28891557
- PMCID: PMC5783317
- DOI: 10.1038/nri.2017.95
Review
Functions of tissue-resident eosinophils
Peter F Weller et al. Nat Rev Immunol. 2017 Dec.
Abstract
Eosinophils are a prominent cell type in particular host responses such as the response to helminth infection and allergic disease. Their effector functions have been attributed to their capacity to release cationic proteins stored in cytoplasmic granules by degranulation. However, eosinophils are now being recognized for more varied functions in previously underappreciated diverse tissue sites, based on the ability of eosinophils to release cytokines (often preformed) that mediate a broad range of activities into the local environment. In this Review, we consider evolving insights into the tissue distribution of eosinophils and their functional immunobiology, which enable eosinophils to secrete in a selective manner cytokines and other mediators that have diverse, 'non-effector' functions in health and disease.
Conflict of interest statement
Competing interests statement
The authors declare no competing interests.
Figures
Figure 1. Eosinophil-derived mediators and their functions
Eosinophils are a source of lipid mediators, granule-derived cationic proteins and a large number of chemokines and cytokines (many of which are stored preformed within eosinophil intracellular granules) that have wide-ranging effects in health and disease. APRIL, a proliferation-inducing ligand; CCL, CC-chemokine ligand; CXCL, CXC-chemokine ligand; DC, dendritic cell; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EPX, eosinophil peroxidase; GM-CSF, granulocyte–macrophage colony-stimulating factor; IFNγ, interferon-γ; MBP1, major basic protein 1; MMP9, matrix metalloproteinase 9; NGF, nerve growth factor; PDGF, platelet-derived growth factor; SCF, stem cell factor; TGF, transforming growth factor; TH, T helper; TIMP1, tissue inhibitor of metalloproteinases 1; TNF, tumour necrosis factor; VEGF, vascular endothelial cell growth factor.
Figure 2. Modes of eosinophil secretion
A | Intracellular granules within non-activated, resting eosinophils have a well-defined, electron-dense crystalline core and an electron-lucent outer matrix, surrounded by a trilaminar membrane. B | Eosinophils adherent to the surface of a large multicellular parasite have been shown to undergo classic exocytotic degranulation, wherein intracellular granules fuse with the plasma membrane, creating a secretory pore through which the entire granule contents are released. In compound exocytosis, granule–granule fusions occur within the cytoplasm, forming secretory channels that enable the wholesale degranulation of the combined content of multiple granules. C | By contrast, piecemeal degranulation (PMD) differentially releases granule-derived proteins, including cytokines, as discrete packets. As shown in panel Ca, granules within cells undergoing PMD exhibit varying degrees of ultrastructural alteration, including an apparent reorganization of electron-dense contents and the appearance of a membranous network of tubules within granules. As shown in panel Cb, granule-derived proteins are differentially mobilized into small round vesicles and tubular structures, the latter termed eosinophil sombrero vesicles (EoSVs), that emerge from mobilized granules and seem to derive directly from the intragranular membrano-vesicular network of tubules. As shown for eotaxin-elicited PMD of IL-4 in panel Cc, tubular EoSVs express lumen-oriented receptor chains that are bound by their cognate cytokine ligand, which indicates that a mechanism of receptor-mediated chaperoning may contribute to differential cytokine secretion. After emerging from granules, cytoplasmic EoSVs and small vesicles traverse the cytoplasm and fuse with the plasma membrane to release their granule-derived cargo. D | Eosinophils may also be induced to undergo a cytolytic cell death pathway characterized by dissolution of the nuclear and plasma membranes, extrusion of DNA nets and expulsion of intact granules that are observed individually and as clusters of cell-free extracellular granules within tissues. A portion of cell-free, extracellularly deposited eosinophil granules retain an intact trilaminar outer membrane, express outwardly oriented functional receptors on their outer membranes as shown in the right panel, and remain competent to undergo stimulus-dependent secretion within tissues.
Figure 3. Ultrastructure of activated human eosinophils and immunolocalization of mobilized MBP1 and IL-4
A | Conventional transmission electron microscopy of an activated eosinophil. In response to stimulation of eosinophils, their secretory granules exhibit structural changes, including the loss of a well-defined crystalline core and the reorganization of electron-dense materials, which is indicative of granule emptying. Aa | Representative granules exhibiting a well-defined electron-dense core (crystalline core) or progressive loss of core (residual core) are indicated. Activated eosinophils contain increased numbers of large tubular carriers (known as eosinophil sombrero vesicles (EoSVs)) that derive from mobilized granules and are seen as elongated, curved or folded circumferential structures (highlighted in pink). Ab | Intragranular membrano-vesicular domains (arrow) give rise to granule-derived small vesicles and EoSVs and are associated with the release of granule-stored products. B,C | Pre-embedding immunonanogold electron microscopy of an eotaxin 1-stimulated eosinophil, showing secretory granules containing major basic protein 1 (MBP1) in progressive stages of emptying (panel Ba). Note the structural disarrangement of the granules in panel Bb and vesicular trafficking of MBP1 in the lumen of large carriers (panel C, arrows). D,E | These carriers (arrows) were labelled for IL-4. Note that IL-4 mobilization is linked to granule and vesicle membranes, which is indicative of binding to cognate IL-4 receptor α-chain. Cells were prepared as described in REFS ,. LB, lipid body; Gr, granule; N, nucleus. Scale bars, 900 nm (panel Aa), 500 nm (panel Ab), 700 nm (panel Ba), 400 nm (panel Bb), 300 nm (panel C), and 200 nm (panels D and E). Electron microscopy images courtesy of R. C. N. Melo, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
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