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Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation.

ABSTRACT: PGD(2) is a key mediator of allergic inflammatory diseases that is mainly synthesized by mast cells, which constitutively express high levels of the terminal enzyme involved in PGD(2) synthesis, the hematopoietic PGD synthase (H-PGDS). In this study, we investigated whether eosinophils are also able to synthesize, and therefore, supply biologically active PGD(2). PGD(2) synthesis was evaluated within human blood eosinophils, in vitro differentiated mouse eosinophils, and eosinophils infiltrating inflammatory site of mouse allergic reaction. Biological function of eosinophil-derived PGD(2) was studied by employing inhibitors of synthesis and activity. Constitutive expression of H-PGDS was found within nonstimulated human circulating eosinophils. Acute stimulation of human eosinophils with A23187 (0.1-5 ?M) evoked PGD(2) synthesis, which was located at the nuclear envelope and was inhibited by pretreatment with HQL-79 (10 ?M), a specific H-PGDS inhibitor. Prestimulation of human eosinophils with arachidonic acid (10 ?M) or human eotaxin (6 nM) also enhanced HQL-79-sensitive PGD(2) synthesis, which, by acting on membrane-expressed specific receptors (D prostanoid receptors 1 and 2), displayed an autocrine/paracrine ability to trigger leukotriene C(4) synthesis and lipid body biogenesis, hallmark events of eosinophil activation. In vitro differentiated mouse eosinophils also synthesized paracrine/autocrine active PGD(2) in response to arachidonic acid stimulation. In vivo, at late time point of the allergic reaction, infiltrating eosinophils found at the inflammatory site appeared as an auxiliary PGD(2)-synthesizing cell population. Our findings reveal that eosinophils are indeed able to synthesize and secrete PGD(2), hence representing during allergic inflammation an extra cell source of PGD(2), which functions as an autocrine signal for eosinophil activation.

SUBMITTER: Luna-Gomes T

PROVIDER: S-EPMC3237921 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation.

Luna-Gomes Tatiana T Magalhães Kelly G KG Mesquita-Santos Fabio P FP Bakker-Abreu Ilka I Samico Rafaela F RF Molinaro Raphael R Calheiros Andrea S AS Diaz Bruno L BL Bozza Patrícia T PT Weller Peter F PF Bandeira-Melo Christianne C

Journal of immunology (Baltimore, Md. : 1950) 20111118 12

PGD(2) is a key mediator of allergic inflammatory diseases that is mainly synthesized by mast cells, which constitutively express high levels of the terminal enzyme involved in PGD(2) synthesis, the hematopoietic PGD synthase (H-PGDS). In this study, we investigated whether eosinophils are also able to synthesize, and therefore, supply biologically active PGD(2). PGD(2) synthesis was evaluated within human blood eosinophils, in vitro differentiated mouse eosinophils, and eosinophils infiltrating ...[more]

PMID: 22102725

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Project description:Eosinophil-lineage committed progenitor cells (EoP) migrate from the bone marrow and differentiate locally to provide an ongoing source of mature eosinophils in asthmatic inflammatory responses in the airways. Sputum levels of EoP are increased in asthmatics compared to normal controls suggesting an exaggerated eosinophilopoietic environment in the airways. Understanding what factors promote EoP traffic to the airways is important to understand the diathesis of asthma pathology. Interleukin (IL)-25, is an epithelial-derived cytokine that promotes type 2 inflammatory responses. We have previously shown that levels of IL-25 and expression of the IL-25 receptor (IL-17RA and IL-17RB) on mature eosinophils are greater in allergic asthmatics compared to atopic non-asthmatics and non-atopic normal controls. In addition, these levels were increased significantly increased following allergen inhalation challenge and physiologically relevant levels of IL-25 stimulated eosinophil degranulation, intracellular IL-5 and IL-13 expression and primed migration to eotaxin. The current study, examined the role of IL-25 on allergen-induced trafficking of EoP in atopic asthmatics.Asthmatics (n = 14) who developed allergen-induced early and late responses were enrolled in the study. Blood was collected at pre- and 24 h post-challenge. At each time point, surface expression of IL-17RA and IL-17RB on EoP was evaluated by flow cytometry. Migration assays examined the effect of IL-25 on EoP chemotactic responses, in vitro. In addition, IL-25 knockout ovalbumin (OVA) sensitized and challenged mice were studied to evaluate in vivo mobilization effects of IL-25 on newly formed EoP and mature eosinophils.There was a significant increase in numbers of blood EoP expressing IL-17RB, 24 h post-allergen inhalation challenge in allergic asthmatics. Pre-exposure to IL-25 primed the migrational responsiveness of EoP to stromal cell-derived factor 1?. In OVA-sensitized mice, knocking out IL-25 significantly alleviated OVA-induced eosinophil infiltration in the airway and newly formed eosinophils were reduced in the lung.The findings of this study indicate a potential role for IL-25 in allergen-induced trafficking of EoP to the airways and local differentiation promoting tissue eosiniophilia in asthmatic responses.

Dataset Information

Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation.

Publications

Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation.

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