Walsh, E.R. et al. Strain-specific requirement for eosinophils in the recruitment of T cells to the lung during the development of allergic asthma. J. Exp. Med. 205, 1285-1292

Center for Molecular Immunology and Infectious Disease and Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 07/2008; 205(6):1285-92. DOI: 10.1084/jem.20071836
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Eosinophils have been implicated as playing a major role in allergic airway responses. However, the importance of these cells to the development of this disease has remained ambiguous despite many studies, partly because of lack of appropriate model systems. In this study, using transgenic murine models, we more clearly delineate a role for eosinophils in asthma. We report that, in contrast to results obtained on a BALB/c background, eosinophil-deficient C57BL/6 Delta dblGATA mice (eosinophil-null mice via the Delta DblGATA1 mutation) have reduced airway hyperresponsiveness, and cytokine production of interleukin (IL)-4, -5, and -13 in ovalbumin-induced allergic airway inflammation. This was caused by reduced T cell recruitment into the lung, as these mouse lungs had reduced expression of CCL7/MCP-3, CC11/eotaxin-1, and CCL24/eotaxin-2. Transferring eosinophils into these eosinophil-deficient mice and, more importantly, delivery of CCL11/eotaxin-1 into the lung during the development of this disease rescued lung T cell infiltration and airway inflammation when delivered together with allergen. These studies indicate that on the C57BL/6 background, eosinophils are integral to the development of airway allergic responses by modulating chemokine and/or cytokine production in the lung, leading to T cell recruitment.

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Available from: Alison Humbles, May 29, 2015
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    • "Since IL-5 and eotaxin-1 are both important for the recruitment of eosinophils [18], we also investigated the eotaxin-1 production in both Wt and Par-2 deficient mice after HDM exposure. Only a significant increase in eotaxin-1 levels of was observed in Wt mice exposed to Citeq HDM, while a trend (p = 0.09) towards significance was observed in mice exposed to the Greer HDM extract (Figure 3E–F). "
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    ABSTRACT: Aeroallergens such as house dust mite (HDM), cockroach, and grass or tree pollen are innocuous substances that can induce allergic sensitization upon inhalation. The serine proteases present in these allergens are thought to activate the protease-activated receptor (PAR)-2, on the airway epithelium, thereby potentially inducing allergic sensitization at the expense of inhalation tolerance. We hypothesized that the proteolytic activity of allergens may play an important factor in the allergenicity to house dust mite and is essential to overcome airway tolerance. Here, we aimed to investigate the role of PAR-2 activation in allergic sensitization and HDM-induced allergic airway inflammation. In our study, Par-2 deficient mice were treated with two different HDM extracts containing high and low serine protease activities twice a week for a period of 5 weeks. We determined airway inflammation through quantification of percentages of mononuclear cells, eosinophils and neutrophils in the bronchial alveolar lavage fluid and measured total IgE and HDM-specific IgE and IgG1 levels in serum. Furthermore, Th2 and pro-inflammatory cytokines including IL-5, IL-13, Eotaxin-1, IL-17, KC, Chemokine (C-C motif) ligand 17 (CCL17) and thymic stromal lymphopoietin (TSLP), were measured in lung tissue homogenates. We observed that independent of the serine protease content, HDM was able to induce elevated levels of eosinophils and neutrophils in the airways of both wild-type (WT) and Par-2 deficient mice. Furthermore, we show that induction of pro-inflammatory cytokines by HDM exposure is independent of Par-2 activation. In contrast, serine protease activity of HDM does contribute to enhanced levels of total IgE, but not HDM-specific IgE. We conclude that, while Par-2 activation contributes to the development of IgE responses, it is largely dispensable for the HDM-induced induction of pro-inflammatory cytokines and airway inflammation in an experimental mouse model of HDM-driven allergic airway disease.
    PLoS ONE 03/2014; 9(3):e91206. DOI:10.1371/journal.pone.0091206 · 3.23 Impact Factor
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    • "Asthmatic endothelial P­selectin can also directly activate eosinophil at­ tachment to the endothelium (Johansson and Mosher, 2011). Eosinophils are required for and can significantly augment the severity of the allergen­induced inflammation by secret­ ing Th2 cytokines (Rosenberg et al., 2007), activating and re­ cruiting T cells (MacKenzie et al., 2001; Mattes et al., 2002; Jacobsen et al., 2008; Walsh et al., 2008), and modulating den­ dritic cell responses (Jacobsen et al., 2008). Additional studies will be required to further define the mechanisms that the VEGF–miR­1–Mpl–P­selectin pathway uses to regulate pul­ monary Th2 responses. "
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    ABSTRACT: Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF-miR-1-Mpl-P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma.
    Journal of Experimental Medicine 09/2013; 210(10). DOI:10.1084/jem.20121200 · 12.52 Impact Factor
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    • "The effect of inhibition of mTOR on the expression of lung chemokines was also assessed. As shown in Figure 4, administration of rapamycin in the induction model significantly reduced the lung mRNA levels of key chemokines that mediate the chemotaxis of eosinophils and T cells to asthmatic lungs via binding to CCR3, including CCL11 (eotaxin-1), CCL24 (eotaxin-2) and CCL7 (MCP-3) [16], [17], [18]. Rapamycin treatment of established asthma, however, increased mRNA levels of CCL11 and did not affect the expression of CCL7 or CCL24. "
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    ABSTRACT: The mammalian target of rapamycin (mTOR) modulates immune responses and cellular proliferation. The objective of this study was to assess whether inhibition of mTOR with rapamycin modifies disease severity in two experimental murine models of house dust mite (HDM)-induced asthma. In an induction model, rapamycin was administered to BALB/c mice coincident with nasal HDM challenges for 3 weeks. In a treatment model, nasal HDM challenges were performed for 6 weeks and rapamycin treatment was administered during weeks 4 through 6. In the induction model, rapamycin significantly attenuated airway inflammation, airway hyperreactivity (AHR) and goblet cell hyperplasia. In contrast, treatment of established HDM-induced asthma with rapamycin exacerbated AHR and airway inflammation, whereas goblet cell hyperplasia was not modified. Phosphorylation of the S6 ribosomal protein, which is downstream of mTORC1, was increased after 3 weeks, but not 6 weeks of HDM-challenge. Rapamycin reduced S6 phosphorylation in HDM-challenged mice in both the induction and treatment models. Thus, the paradoxical effects of rapamycin on asthma severity paralleled the activation of mTOR signaling. Lastly, mediastinal lymph node re-stimulation experiments showed that treatment of rapamycin-naive T cells with ex vivo rapamycin decreased antigen-specific Th2 cytokine production, whereas prior exposure to in vivo rapamycin rendered T cells refractory to the suppressive effects of ex vivo rapamycin. We conclude that rapamycin had paradoxical effects on the pathogenesis of experimental HDM-induced asthma. Thus, consistent with the context-dependent effects of rapamycin on inflammation, the timing of mTOR inhibition may be an important determinant of efficacy and toxicity in HDM-induced asthma.
    PLoS ONE 05/2012; 7(5):e33984. DOI:10.1371/journal.pone.0033984 · 3.23 Impact Factor
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