Eosinophil-derived IFN-γ induces airway hyperresponsiveness and lung inflammation in the absence of lymphocytes

Kanda, Akira; Driss, Virginie; Hornez, Nicolas; Abdallah, Marwan; Roumier, Thomas; Abboud, Georges; Legrand, Fanny; Staumont‐Sallé, D.; Quéant, Severine; Bertout, Julie; Fleury, Sébastien; Rémy, Patrick; Papin, Jean-Paul; Julia, Valérie; Capron, Moníque; Dombrowicz, David

doi:10.1016/j.jaci.2009.04.031

Cited by 65 publications

(48 citation statements)

References 38 publications

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“…The increased IFN-␥ mRNA levels correlated with a reduction in Th2-type cytokine expression in the immunized and RSV-challenged knockout mice; however, IFN-␥ expression did not appear to play a substantial role in counterbalancing Th2 cytokine expression in FI-RSV-immunized IL-5Tg mice challenged with RSV. A possible explanation could be that excessive production of IL-5 in FI-RSVimmunized IL-5Tg mice challenged with RSV may induce more IFN-␥ for immune homeostasis (39). At the protein level, unimmunized RSV-infected WT mice had IFN-␥ levels similar to those of the unimmunized knockout mouse groups challenged with RSV (Fig.…”

Section: Deficiency In Il-5 and Eotaxin Reduces Immunohistopathology mentioning

confidence: 84%

Dual Proinflammatory and Antiviral Properties of Pulmonary Eosinophils in Respiratory Syncytial Virus Vaccine-Enhanced Disease

Townsend

Herrero

et al. 2015

J Virol

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Human respiratory syncytial virus (RSV) is a major cause of morbidity and severe lower respiratory tract disease in the elderly and very young, with some infants developing bronchiolitis, recurrent wheezing, and asthma following infection. Previous studies in humans and animal models have shown that vaccination with formalin-inactivated RSV (FI-RSV) leads to prominent airway eosinophilic inflammation following RSV challenge; however, the roles of pulmonary eosinophilia in the antiviral response and in disease pathogenesis are inadequately understood. In vivo studies in mice with eotaxin and/or interleukin 5 (IL-5) deficiency showed that FI-RSV vaccination did not lead to enhanced pulmonary disease, where following challenge there were reduced pulmonary eosinophilia, inflammation, Th2-type cytokine responses, and altered chemokine (TARC and CCL17) responses. In contrast to wild-type mice, RSV was recovered at high titers from the lungs of eotaxin-and/or IL-5-deficient mice. Adoptive transfer of eosinophils to FI-RSV-immunized eotaxin-and IL-5-deficient (double-deficient) mice challenged with RSV was associated with potent viral clearance that was mediated at least partly through nitric oxide. These studies show that pulmonary eosinophilia has dual outcomes: one linked to RSV-induced airway inflammation and pulmonary pathology and one with innate features that contribute to a reduction in the viral load. IMPORTANCEThis study is critical to understanding the mechanisms attributable to RSV vaccine-enhanced disease. This study addresses the hypothesis that IL-5 and eotaxin are critical in pulmonary eosinophil response related to FI-RSV vaccine-enhanced disease. The findings suggest that in addition to mediating tissue pathology, eosinophils within a Th2 environment also have antiviral activity. R espiratory syncytial virus (RSV) is a serious lower respiratory tract infection in infants, the elderly, and the immunocompromised (1-4), resulting in Ͼ130,000 hospitalizations in the United States each year (5, 6). Children who experience acute RSV infection of the lower respiratory tract have an increased likelihood of developing childhood asthma (7). To date, there is no safe and effective RSV vaccine available. This is in part linked to the negative outcome of a 1960s clinical trial using a formalin-inactivated alum-precipitated RSV (FI-RSV) vaccine (8). Children immunized with the FI-RSV vaccine experienced more severe disease following subsequent natural exposure to RSV, with one study showing 69% of immunized children developing pneumonia compared to only 9% of children in the unimmunized control group (9). In a second study, 80% of FI-RSV-immunized infants were hospitalized and two died, compared with only 5% hospitalization and no death in the control group (10). FI-RSV vaccineenhanced illness was clinically characterized as severe primary RSV infection, with bronchiolitis, hypoxemia, and pneumonia. However, in contrast to the neutrophilic inflammation observed during primary RSV infection, the more severe a...

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Section: Deficiency In Il-5 and Eotaxin Reduces Immunohistopathology mentioning

confidence: 84%

Dual Proinflammatory and Antiviral Properties of Pulmonary Eosinophils in Respiratory Syncytial Virus Vaccine-Enhanced Disease

Townsend

Herrero

et al. 2015

J Virol

View full text Add to dashboard Cite

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“…Thus, in mouse studies, IL-5 transgenic mice provide the only source of mouse eosinophils that can be used for measuring eosinophil effector functions in vitro. Our studies on eosinophils from IL-5 transgenic mice are not unprecedented for analyzing effector functions of these cells [28,43]. …”

Section: Discussionmentioning

confidence: 99%

Agonist Activation of F-Actin-Mediated Eosinophil Shape Change and Mediator Release Is Dependent on Rac2

Lacy

Willetts

Kim

et al. 2011

Int Arch Allergy Immunol

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Background: Tissue recruitment and activation of eosinophils contribute to allergic symptoms by causing airway hyperresponsiveness and inflammation. Shape changes and mediator release in eosinophils may be regulated by mammalian Rho-related guanosine triphosphatases. Of these, Rac2 is essential for F-actin formation as a central process underlying cell motility, exocytosis, and respiratory burst in neutrophils, while the role of Rac2 in eosinophils is unknown.We set out to determine the role of Rac2 in eosinophil mediator release and F-actin-dependent shape change in response to chemotactic stimuli. Methods: Rac2-deficient eosinophils from CD2-IL-5 transgenic mice crossed with rac2 gene knockout animals were examined for their ability to release superoxide through respiratory burst or eosinophil peroxidase by degranulation. Eosinophil shape change and actin polymerization were also assessed by flow cytometry and confocal microscopy following stimulation with eotaxin-2 or platelet-activating factor. Results: Eosinophils from wild-type mice displayed inducible superoxide release, but at a small fraction (4–5%) of human eosinophils. Rac2-deficient eosinophils showed significantly less superoxide release (p < 0.05, 26% less than wild type). Eosinophils lacking Rac2 had diminished degranulation (p < 0.05, 62% less eosinophil peroxidase) and shape changes in response to eotaxin-2 or platelet-activating factor (with 68 and 49% less F-actin formation, respectively; p < 0.02) compared with wild-type cells. Conclusion: These results demonstrate that Rac2 is an important regulator of eosinophil function by contributing to superoxide production, granule protein release, and eosinophil shape change. Our findings suggest that Rho guanosine triphosphatases are key regulators of cellular inflammation in allergy and asthma.

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“…2E), supporting the conclusion that IFN-g-producing-iNKT cells counteract IL-33-driven lung inflammation. IFN-g is generally considered a pro-rather than an antiinflammatory factor, including in the airways where it contributes to the development of antigen-induced allergic asthma when produced by eosinophils or Ag-specific CD4 1 Th1 cells [25,26]. It might be speculated that these divergent effects depending on the cellular source result from the unique capacity of iNKT cells activated by a-GC, to produce concomitantly IFN-g and IL-27 [27], a cytokine belonging to the IL-12 family [28].…”

Section: The Anti-inflammatory Action Of Inkt Cells Is Driven By Theimentioning

confidence: 99%

A natural protective function of invariant NKT cells in a mouse model of innate‐cell‐driven lung inflammation

et al. 2011

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Activation of invariant natural killer T (iNKT) cells by treatment with their a-galactosylceramide ligand provides therapeutic benefits in several immune inflammatory settings. Given the artificial nature of this stimulation, the natural regulatory functions of iNKT remain uncertain. Addressing this issue in a mouse model of innate-cell-driven lung inflammation induced by the cytokine/alarmin IL-33 that targets iNKT cells, we found that eosinophil and neutrophil recruitment was markedly increased in treated iNKT cell-deficient (Ja18 KO) mice, as was the local production of eotaxin and keratinocyte chemoattractant chemokines. By contrast, lung inflammation decreased after adoptive transfer of iNKT cells, which restored the WT inflammatory response in Ja18 KO mice. Finally, we established that this natural anti-inflammatory function of iNKT cells depends on their IFN-c production and on endogenous IL-12. Our study provides the first evidence of a protective role of iNKT cells during lung inflammation that does not require pharmacological TCR engagement.Keywords: IL-33 . Inflammation . iNKT cells . Innate cells Supporting Information available online IntroductionInvariant natural killer T (iNKT) cells constitute a population of T cells, which share some characteristics with NK cells. In this regard, they occupy a strategic position between adaptive and innate immunity. iNKT cells are characterized by the expression of an invariant Va14Ja18 antigen receptor, chiefly paired with Vb8.2 in mice and of the invariant Va24Ja18/Vb11 pair in humans (for reviews see [1,2] Frontline key regulatory functions, based on the therapeutic benefits provided by their specific exogenous ligand a-galactosyl ceramide (a-GC) in several models of autoimmunity and allergic asthma (for reviews see [5][6]) [7][8][9][10][11]. However, whether these cells actually play a regulatory role in these pathologies in the absence of pharmacological TCR engagement is still doubtful (for reviews see [6]). The answer to this fundamental question in iNKT cell biology has remained elusive since almost all pathological experimental models of autoimmunity and asthma require an immunization phase that presumably recruits and activates iNKT cells in a non-physiological rather than a disease-specific manner. Hence, there is still no definite evidence that iNKT cells specifically exert natural regulatory functions in the experimental allergic OVA-or ragweed-induced asthma model, in which iNKT cells can promote disease protection [10,11] or induction and/or exacerbation [12][13][14], depending on their mode of activation.Here, we used a novel approach to address this issue in a model of innate-cell-driven lung inflammation induced by , a cytokine that has recently been described as a member of the IL-1 family [16] and credited with alarmin functions [17][18][19]. This strategy is of pathophysiological relevance, considering the well-established role played by iNKT cells during allergic asthma together with the fact that they are effectively targeted and functiona...

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Eosinophil-derived IFN-γ induces airway hyperresponsiveness and lung inflammation in the absence of lymphocytes

Cited by 65 publications

References 38 publications

Dual Proinflammatory and Antiviral Properties of Pulmonary Eosinophils in Respiratory Syncytial Virus Vaccine-Enhanced Disease

Dual Proinflammatory and Antiviral Properties of Pulmonary Eosinophils in Respiratory Syncytial Virus Vaccine-Enhanced Disease

Agonist Activation of F-Actin-Mediated Eosinophil Shape Change and Mediator Release Is Dependent on Rac2

A natural protective function of invariant NKT cells in a mouse model of innate‐cell‐driven lung inflammation

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