Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of diverse inflammatory responses, as well as modulators of innate and adaptive immunity. In this review, the biology of eosinophils is summarized, focusing on transcriptional regulation of eosinophil differentiation, characterization of the growing properties of eosinophil granule proteins, surface proteins and pleiotropic mediators, and molecular mechanisms of eosinophil degranulation. New views on the role of eosinophils in homeostatic function are examined, including developmental biology and innate and adaptive immunity (as well as their interaction with mast cells and T cells) and their proposed role in disease processes including infections, asthma, and gastrointestinal disorders. Finally, strategies for targeted therapeutic intervention in eosinophil-mediated mucosal diseases are conceptualized.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2222.2008.02958.x

Eosinophils: Biological Properties and Role in Health and Disease

Atopic dermatitis (AD) is a chronic inflammatory skin disease that frequently predates the development of allergic rhinitis or asthma. It is an important skin condition with significant costs and morbidity to patients and their families; the disease affects more than 10% of children. Recent studies have demonstrated the complex interrelationship of genetic, environmental, skin barrier, pharmacologic, psychologic, and immunologic factors that contribute to the development and severity of AD. The current review will examine the cellular and molecular mechanisms that contribute to AD as well as the immunologic triggers involved in its pathogenesis. These insights provide new opportunities for therapeutic intervention in this common skin condition. (J Allergy Clin Immunol 2000;105:860-76.)

https://www.jacionline.org/article/S0091-6749(00)80006-8/pdf

Atopic dermatitis: New insights and opportunities for therapeutic intervention

Pharmacology of the Eosinophil

We recently discovered that a ubiquitous protein, high mobility group box 1 protein (HMGB1), is released by activated macrophages, and functions as a late mediator of lethal systemic inflammation. To elucidate mechanisms underlying the regulation of HMGB1 release, we examined the roles of other cytokines in induction of HMGB1 release in macrophage cell cultures. Macrophage migration inhibitory factor, macrophage-inflammatory protein 1beta, and IL-6 each failed to significantly induce the release of HMGB1 even at supraphysiological levels (up to 200 ng/ml). IFN-gamma, an immunoregulatory cytokine known to mediate the innate immune response, dose-dependently induced the release of HMGB1, TNF, and NO, but not other cytokines such as IL-1alpha, IL-1beta, or IL-6. Pharmacological suppression of TNF activity with neutralizing Abs, or genetic disruption of TNF expression (TNF knockout) partially (50-60%) inhibited IFN-gamma-mediated HMGB1 release. AG490, a specific inhibitor for Janus kinase 2 of the IFN-gamma signaling pathway, dose-dependently attenuated IFN-gamma-induced HMGB1 release. These data suggest that IFN-gamma plays an important role in the regulation of HMGB1 release through a TNF- and Janus kinase 2-dependent mechanism.

/pdf/ifn-g-induces-high-mobility-group-box-1-protein-release-3qnn0bplb5.pdf

IFN-γ Induces High Mobility Group Box 1 Protein Release Partly Through a TNF-Dependent Mechanism

Eosinophils derive from the bone marrow and circulate at low levels in the blood in healthy individuals. These granulated cells preferentially leave the circulation and marginate to tissues, where they are implicated in the regulation of innate and adaptive immunity. In diseases such as allergic inflammation, eosinophil numbers escalate markedly in the blood and tissues where inflammatory foci are located. Eosinophils possess a range of immunomodulatory factors that are released upon cell activation, including over 35 cytokines, growth factors, and chemokines. Unlike T and B cells, eosinophils can rapidly release cytokines within minutes in response to stimulation. While some cytokines are stored as pre-formed mediators in crystalloid granules and secretory vesicles, eosinophils are also capable of undergoing de novo synthesis and secretion of these immunological factors. Some of the molecular mechanisms that coordinate the final steps of cytokine secretion are hypothesized to involve binding of membrane fusion complexes comprised of soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs). These intracellular receptors regulate the release of granules and vesicles containing a range of secreted proteins, among which are cytokines and chemokines. Emerging evidence from both human and animal model-based research has suggested an active participation of eosinophils in several physiological/pathological processes such as immunomodulation and tissue remodeling. The observed eosinophil effector functions in health and disease implicate eosinophil cytokine secretion as a fundamental immunoregulatory process. The focus of this review is to describe the cytokines, growth factors, and chemokines that are elaborated by eosinophils, and to illustrate some of the intracellular events leading to the release of eosinophil-derived cytokines.

/pdf/eosinophil-cytokines-chemokines-and-growth-factors-emerging-yv60yaipnl.pdf

Eosinophil Cytokines, Chemokines, and Growth Factors: Emerging Roles in Immunity

In order to determine whether or not IFN-γR is associated with regulatory mechanisms on human eosinophil function, we examined the expression of functional IFN-γR on human peripheral eosinophils. In this study, peripheral blood eosinophils were obtained from seven normal controls and 12 patients (bronchial asthma, n = 9, and hypereosinophilic syndrome (HES), n = 3), and the purity of eosinophils was 97.11 ± 2. 31%, n = 19. We first showed that anti-IFN-γR α-chain MoAb reacted with all tested eosinophils of both normal controls and patients by flow cytometry analysis. We also showed expression of mRNA for the α-chain of IFN-γR in all purified eosinophils of six individuals. Further, to characterize IFN-γR on eosinophils, we did binding experiments with 125I-IFN-γ on purified peripheral eosinophils. The linear Scatchard plot indicated a single type of high-affinity binding sites (dissociation constant (Kd) = 3.89–4.95 × 10−10 m, numbers of binding sites = 183–233/cell, n = 3). To determine whether IFN-γR on eosinophils is functional, we examined surface eosinophilic cationic protein (ECP) and CD69 induction after IFN-γR ligation with recombinant human IFN-γ (rhIFN-γ) on eosinophils by flow cytometry. rhIFN-γ stimulation significantly induced both ECP and CD69 expression on the 2–18 h-cultured eosinophils in a dose-dependent manner. Further, the effects of rhIFN-γ stimulation were significantly blocked by both a neutralizing anti-IFN-γ MoAb and a blocking anti-IFN-γR MoAb. These results suggest that human peripheral eosinophils express functional IFN-γR.

Human peripheral eosinophils express functional interferon-gamma receptors (IFN-γR)

The purpose of this study was to determine whether the JAK pathway is involved in eosinophil activation and survival through IFN-γ receptor signalling in human peripheral eosinophils. Eosinophils were purified from the blood of six atopic disease patients by anti-CD16 magnetic bead-negative selection. IFN-γ significantly up-regulated survival and CD69 expression in 24–48 h cultured eosinophils. Further, IFN-γ induced tyrosine phosphorylation of JAK2 in eosinophils, as indicated by Western blot analysis. Finally, the specific JAK2 inhibitor AG-490 inhibited the tyrosine phosphorylation of JAK2, IFN-γ-induced survival and CD69 expression in eosinophils. In conclusion, these results indicate that IFN-γ induces eosinophil survival and CD69 expression through the activation of JAK2 in peripheral eosinophils, suggesting that JAK2 may play a significant role in eosinophil regulation by IFN-γ–IFN-γR interaction.

Role of JAK2 signal transductional pathway in activation and survival of human peripheral eosinophils by interferon-gamma (IFN-γ)

Background: We reported on the constitutive interferon–γ receptor (IFN–γR) expression on eosinophils. But signal transduction through IFN–γR on eosinophils remains to be elucidated. In this study, we examined the involvement of the Jak/Stat pathway in the signaling of eosinophils after IFN–γR conjugation by the ligand binding. Methods: Purified peripheral eosinophils were stimulated with IFN–γ at 37°C for 1–60 min. Tyrosine phosphorylation of IFN–γR, Jak1, Jak2, and Stat1α was examined by immunoblotting. Gel–shift assay was also examined to show the formation of Stat1α–DNA complexes. Results: We show that binding of IFN–γ to human eosinophils initiated a series of events that resulted in the rapid tyrosine phosphorylation of not only the IFN–γRα chain but also Jak1, Jak2, and Stat1α. In addition, IFN–γ enhanced the DNA–binding activity of Stat1α. Conclusion: These data indicate that IFN–γ affects eosinophils through its specific receptor and utilizes the Jak/Stat pathway as its mode of signaling.

Signal Transduction through Interferon–Gamma Receptor on Human Eosinophils

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Human peripheral eosinophils express functional interferon-gamma receptors (IFN-γR)

Role of JAK2 signal transductional pathway in activation and survival of human peripheral eosinophils by interferon-gamma (IFN-γ)

Signal Transduction through Interferon–Gamma Receptor on Human Eosinophils