Eosinophils: Singularly destructive effector cells or purveyors of immunoregulation?

Jacobsen, Elizabeth A.; Taranova, Anna G.; Lee, Nancy A.; Lee, James J.

doi:10.1016/j.jaci.2007.03.043

Cited by 184 publications

(144 citation statements)

References 49 publications

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“…Similarly, a study 10 using anti-IL-5 treatment showed an association of eosinophil frequency with susceptibility during cryptococcosis. During the past decade, several reports 77,78 extended the function of eosinophils beyond the sole defense against nonphagotizable pathogens. Eosinophils produced various chemokines and cytokines modulating immune responses in different models.…”

Section: Discussionmentioning

confidence: 99%

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

Piehler

Stenzel

Grahnert

et al. 2011

The American Journal of Pathology

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Susceptibility to infection with Cryptococcus neoformans is tightly determined by production of IL-4. In this study, we investigated the time course of IL-4 production and its innate cellular source in mice infected intranasally with C. neoformans. We show that pulmonary IL-4 production starts surprisingly late after 6 weeks of infection. Interestingly, in the lungs of infected mice, pulmonary T helper (Th) cells and eosinophils produce significant amounts of IL-4. In eosinophil-deficient ⌬dblGATA mice, IL-33 receptor-expressing Th2s are significantly reduced, albeit not absent, whereas protective Th1 and Th17 responses are enhanced. In addition, recruitment of pulmonary inflammatory cells during infection with C. neoformans is reduced in the absence of eosinophils. These data expand previous findings emphasizing an exclusively destructive effector function by eosinophilic granulocytes. Moreover, in ⌬dblGATA mice, fungal control is slightly enhanced in the lung; however, dissemination of Cryptococcus is not prevented. Therefore, eosinophils play an immunoregulatory role that contributes to Th2-dependent susceptibility in allergic inflammation during bronchopulmonary mycosis. Cryptococcus neoformans is a facultative intracellular pathogen that is acquired by inhalation of spores and/or desiccated yeasts and leads to latent pulmonary infection in immunocompetent humans. 1 The development of cryptococcal meningitis occurs mainly in immunocompromised HIV-1-infected patients, most likely by reactivation of latent pulmonary C. neoformans infection. 2 It is estimated that 504,000 HIV-1-infected patients die every year from cryptococcal meningitis in sub-Saharan Africa, 3 which surprisingly exceeds the annual death rate of tuberculosis-associated HIV cases. Resistance against C. neoformans primarily involves monocytic effector mechanisms. 4 -6 In this context, T helper (Th) cells are central regulatory players with profound effects. Whereas IL-12-dependent Th1 responses are protective, with an additional contribution by IL-23-dependent Th17 responses, 7-9 Th2 cells producing IL-4, IL-13, and IL-5 are detrimental. 10,11 Studies 12-14 that used i.v. inoculation examined the traversal of the blood-brain barrier by C. neoformans and led to the conclusion that transmigration can occur with intracellular and extracellular fungi. In case of bronchopulmonary infection, dissemination seems to rely more on Th2 cytokines. This allergic Th2-driven inflammation represents the immunopathological pathway promoting disease by allowing cryptococci to grow inside the lung and finally enabling dissemination to the brain, ultimately causing fatal meningoencephalitis. 15 This sequela is accompanied by development of IL-4/IL-13-dependent alternatively activated macrophages, suggesting that those cells may be involved in dissemination. Alternatively activated macrophages are found only in susceptible mice 15 and show significantly reduced control of intracellular growth. 5 In addition, IL-13-dependent mucus production by goblet cells, IL-4 -...

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Section: Discussionmentioning

confidence: 99%

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

Piehler

Stenzel

Grahnert

et al. 2011

The American Journal of Pathology

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“…Cells were grown at 37˚C in 5% CO 2 in culture medium RPMI 1640 without phenol red (supplemented with 10% FCS, 25 mM HEPES buffer, 2 mM L-glutamine, 10 mM sodium pyruvate, and 10 mg/ml gentamycin), hereafter referred to as complete medium (CM). Adherent tumor cells were harvested from the culture flasks posttreatment with 0.05% trypsin EDTA at 37˚C, followed by one wash in CM.…”

Section: Cell Line and Reagentsmentioning

confidence: 99%

“…E osinophils are multifunctional granulocytes mainly involved in helminth infections and allergic diseases (1,2). However, in many cancers, notably in carcinoma, eosinophils recruitment, commonly referred to as tumor-associated tissue eosinophilia (TATE), has been observed in some patients in tumor vicinity (3,4).…”

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confidence: 99%

Human Eosinophils Exert TNF-α and Granzyme A-Mediated Tumoricidal Activity toward Colon Carcinoma Cells

Legrand

Driss

Delbeke

et al. 2010

The Journal of Immunology

144

135

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Peripheral blood and tissue eosinophilia is a prominent feature in allergic diseases and helminth infections. In cancer patients, tumor-associated tissue eosinophilia is frequently observed. Tumor-associated tissue eosinophilia can be associated with a favorable prognosis, notably in colorectal carcinoma. However, underlying mechanisms of eosinophil contribution to antitumor responses are poorly understood. We have in this study investigated the direct interactions of human eosinophils with Colo-205, a colorectal carcinoma cell line, and show that eosinophils induce apoptosis and directly kill tumor cells. Using blocking Abs, we found that CD11a/CD18 complex is involved in the tumoricidal activity. Coculture of eosinophils with Colo-205 led to the release of eosinophil cationic protein and eosinophil-derived neurotoxin as well as TNF-α secretion. Moreover, eosinophils expressed granzyme A, which was released upon interaction with Colo-205, whereas cytotoxicity was partially inhibited by FUT-175, an inhibitor of trypsin-like enzymatic activity. Our data present the first demonstration, to our knowledge, that granzyme A is a cytotoxic mediator of the eosinophil protein arsenal, exerting eosinophil tumoricidal activity toward Colo-205, and provide mechanistic evidence for innate responses of eosinophil against tumor cells.

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“…The infiltrating eosinophils release several toxic and proinflammatory mediators which induce epithelial injury, airway hyper-responsiveness, and airway remodeling [6][7][8]. Therefore, eosinophils are regarded as potential therapeutic targets in allergic diseases and asthma [9].…”

Section: Introductionmentioning

confidence: 99%

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

et al. 2011

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Eosinophil extravasation across the endothelium is a key feature of allergic inflammation. Here, we investigated the role of PGE 2 and its receptor, E-type prostanoid receptor (EP)-4, in the regulation of eosinophil interaction with human pulmonary microvascular endothelial cells. PGE 2 and the EP4 receptor agonist ONO AE1-329 significantly reduced eotaxininduced eosinophil adhesion to fibronectin, and formation of filamentous actin and gelsolin-rich adhesive structures. These inhibitory effects were reversed by a selective EP4 receptor antagonist, ONO AE3-208. PGE 2 and the EP4 agonist prevented the activation and cell-surface clustering of b2 integrins, and L-selectin shedding of eosinophils. Under physiological flow conditions, eosinophils that were treated with the EP4 agonist showed reduced adhesion to endothelial monolayers upon stimulation with eotaxin, as well as after TNF-a-induced activation of the endothelial cells. Selective activation of EP1, EP2, and EP3 receptors did not alter eosinophil adhesion to endothelial cells, whereas the EP4 antagonist prevented PGE 2 from decreasing eosinophil adhesion. Finally, eosinophil transmigration across thrombin-and TNF-a-activated endothelial cells was effectively reduced by the EP4 agonist. These data suggest that PGE 2 -EP4 signaling might be protective against allergic responses by inhibiting the interaction of eosinophils with the endothelium and might hence be a useful therapeutic option for controlling inappropriate eosinophil infiltration.Keywords: Adhesion . Endothelium . Eosinophils . Migration . Prostaglandins Supporting Information available online IntroductionEosinophil granulocytes are important effector cells in allergic inflammation and are recruited to the tissue by chemotactic signals [1][2][3][4][5]. The infiltrating eosinophils release several toxic and proinflammatory mediators which induce epithelial injury, airway hyper-responsiveness, and airway remodeling [6][7][8]. Therefore, eosinophils are regarded as potential therapeutic targets in allergic diseases and asthma [9].Prostaglandins (PGs) play diverse roles in inflammation, depending on the cellular context, the type of PG being released, and the differential expression of PG receptors [10,11]. While PGD 2, which is the predominant PG formed in mast cells, exerts proinflammatory effects by regulating the recruitment of eosino- Eur. J. Immunol. 2011. 41: 2379-2389 DOI 10.1002 Leukocyte signaling 2379 phils, basophils, and Th2 lymphocytes to the sites of allergic inflammation [12], PGE 2 seems to attenuate inflammatory responses and reduce tissue injury in airways [13]. PGE 2 was found to exert bronchoprotective effects in patients with asthma [14]. In rats, the ovalbumin-induced early and late phase airway responses were inhibited by intratracheally administered PGE 2 [15]. The activity of PGE 2 is mediated by four subtypes of E-type prostanoid receptors (EP), EP1, EP2, EP3, and EP4 [16]. These G protein-coupled receptors have distinct biological imprints depending on their affinity with...

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Eosinophils: Singularly destructive effector cells or purveyors of immunoregulation?

Cited by 184 publications

References 49 publications

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

Human Eosinophils Exert TNF-α and Granzyme A-Mediated Tumoricidal Activity toward Colon Carcinoma Cells

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

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