Experimental Asthma Research Articles

PARP inhibition by olaparib or gene knockout blocks asthma manifestation in mice by modulating CD4+ T cell function (HYP2P.324)

Abstract An important portion of asthmatics do not respond to current therapies. Thus, the need for new therapeutic drugs becomes urgent. We have demonstrated a critical role for PARP in experimental asthma. In the current study, we test the efficacy of Olaparib, a PARP inhibitor, recently introduced in clinical trials against cancer in blocking established asthma traits in animal models of the disease and determine the mechanism by which it achieves such protection. We show that administration of olaparib in mice post-challenge conferred a robust reduction in airway eosinophilia, mucus production and hyperresponsiveness even after repeated challenges with ovalbumin. The protective effects of olaparib were linked to a suppression of Th2 cytokines and ova-specific IgE with an increase in the Th1 cytokine IFN-g. These traits were associated with a decrease in splenic CD4+T cells and concomitant increase in T-regulatory cells. Adoptive transfer of Th2-skewed OT-II-WT CD4+T cells reversed both Th2 and Th1 cytokines and ova-specific IgE production in ovalbumin-challenged naïve PARP-1-/- mice suggesting a role for PARP-1 in CD4+T but not B cells. Our ex vivo studies show that olaparib treatment markedly reduced CD3/CD28-stimulated gata-3 and il4 expression in Th2-skewed CD4+T cells while causing an elevation in t-bet and ifn-g expression in Th1-skewed CD4+T cells. Our findings show the potential of PARP inhibition as a viable therapeutic strategy to be tested in human clinical trials

MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying PI3K-mediated suppression of HDAC2 (HYP7P.262)

Abstract BACKGROUND: Severe, steroid-insensitive (SSI) asthma is a substantial clinical problem. Effective treatments are urgently required, however, their development is hampered by a lack of understanding of the mechanisms that promote disease. SSI asthma is associated with respiratory infections and non-eosinophilic endotypes of disease, including neutrophilic asthma. OBJECTIVES: To develop and use mouse models of SSI neutrophilic asthma to investigate pathogenic mechanisms involving microRNA (miR)-21, phosphoinositide-3-kinase (PI3K) and histone deacetylase (HDAC)2 in order to identify new therapeutic approaches. METHODS: Novel mouse models of respiratory infection and ovalbumin-induced, SSI neutrophilic allergic airway disease (SSIAAD) in BALB/c mice were developed. The roles of infection-induced miR-21 expression and PI3K-dependent signalling in the lung were examined using a specific miR-21 inhibitor (antagomir-21) and the pan-PI3K inhibitor LY294002. RESULTS: Infection induced a miR-21-dependent, PI3K-mediated signalling pathway that decreased nuclear HDAC2 levels and promoted steroid-insensitive neutrophilic inflammation and airway hyper-responsiveness (AHR) in AAD. Inhibition of miR-21 or PI3K suppressed nuclear pAkt levels and restored HDAC2 levels and steroid sensitivity. CONCLUSIONS: We have identified a novel role for a miR-21/PI3K/HDAC2 signalling axis in SSIAAD. Our data highlights miR-21 as a novel target for treating this form of asthma.

Allergen-induced IL-6 trans-signaling activates γδ T cells to promote type 2 and type 17 airway inflammation

A variant in the IL-6 receptor (IL-6R) gene increases asthma risk and is predicted to decrease IL-6 classic signaling and increase IL-6 trans-signaling. This suggests that inhibition of IL-6 trans-signaling, but not classic signaling, might suppress allergic airway inflammation. We sought to determine whether IL-6 signaling contributes to (1) acute experimental asthma induced by clinically relevant allergens and (2) variation in asthma clinical phenotypes in asthmatic patients. Mice were sensitized to house dust mite (HDM) or cockroach at day 0, treated with IL-6R inhibitors at day 13, and challenged with the same allergen at days 14 to 17. End points were measured 3 hours after the final challenge. IL-6 and soluble IL-6 receptor (sIL-6R) expression in induced sputum of asthmatic patients was correlated with asthma clinical phenotypes. Both HDM and cockroach induced a type 2/type 17 cytokine profile and mixed granulocytic inflammation in the airways. Both allergens increased IL-6 expression in the airways, but only cockroach induced sIL-6R expression. Therefore HDM challenge promoted IL-6 classic signaling but not trans-signaling; in this model treatment with anti-IL-6R did not suppress airway inflammation. In contrast, cockroach-induced inflammation involved activation of IL-6 trans-signaling and production of IL-17A by γδ T cells. Anti-IL-6R, selective blockade of sIL-6R, or γδ T-cell deficiency significantly attenuated cockroach-induced inflammation. Asthmatic patients with high airway IL-6 and sIL-6R levels were enriched for the neutrophilic and mixed granulocytic subtypes. Experimental asthma associated with both high IL-6 and high sIL-6R levels in the airways is attenuated by treatment with IL-6R inhibitors.

Vanin-1 expression and methylation discriminate pediatric asthma corticosteroid treatment response

There is considerable heterogeneity in asthma treatment response. We sought to identify biomarkers of corticosteroid treatment response in children with asthma and evaluate the utility and mechanistic basis of these biomarkers. Children (5-18 years) presenting to the emergency department with an acute asthma exacerbation were recruited and followed during hospitalization. Nasal epithelial cells were collected on presentation to the emergency department (T0) and 18 to 24 hours later (T1), and T1/T0 gene expression ratios were analyzed to identify genes associated with good and poor corticosteroid treatment response phenotypes. The utility of these genes in discriminating between systemic corticosteroid treatment response groups was then tested prospectively in a new cohort of patients. A gene candidate (vanin-1 [VNN1]) that consistently distinguished good versus poor response phenotypes was further studied in an experimental asthma model, and VNN1 promoter methylation was measured by means of bisulfite pyrosequencing in patients. VNN1 mRNA expression changes were associated with systemic corticosteroid treatment response in children with acute asthma, and VNN1 was required for optimal response to corticosteroid treatment in an experimental asthma model. A CpG site within the VNN1 promoter was differentially methylated between good versus poor treatment response groups, and methylation at this site correlated with VNN1 mRNA expression. We have identified a biological basis for poor corticosteroid treatment response that can be used to distinguish a subgroup of asthmatic children who respond poorly to systemic corticosteroid treatment. VNN1 contributes to corticosteroid responsiveness, and changes in VNN1 nasal epithelial mRNA expression and VNN1 promoter methylation might be clinically useful biomarkers of treatment response in asthmatic children.

Collaborative interactions between type 2 innate lymphoid cells and antigen-specific CD4+ Th2 cells exacerbate murine allergic airway diseases with prominent eosinophilia.

Type-2 innate lymphoid cells (ILC2s) and the acquired CD4(+) Th2 and Th17 cells contribute to the pathogenesis of experimental asthma; however, their roles in Ag-driven exacerbation of chronic murine allergic airway diseases remain elusive. In this study, we report that repeated intranasal rechallenges with only OVA Ag were sufficient to trigger airway hyperresponsiveness, prominent eosinophilic inflammation, and significantly increased serum OVA-specific IgG1 and IgE in rested mice that previously developed murine allergic airway diseases. The recall response to repeated OVA inoculation preferentially triggered a further increase of lung OVA-specific CD4(+) Th2 cells, whereas CD4(+) Th17 and ILC2 cell numbers remained constant. Furthermore, the acquired CD4(+) Th17 cells in Stat6(-/-)/IL-17-GFP mice, or innate ILC2s in CD4(+) T cell-ablated mice, failed to mount an allergic recall response to OVA Ag. After repeated OVA rechallenge or CD4(+) T cell ablation, the increase or loss of CD4(+) Th2 cells resulted in an enhanced or reduced IL-13 production by lung ILC2s in response to IL-25 and IL-33 stimulation, respectively. In return, ILC2s enhanced Ag-mediated proliferation of cocultured CD4(+) Th2 cells and their cytokine production, and promoted eosinophilic airway inflammation and goblet cell hyperplasia driven by adoptively transferred Ag-specific CD4(+) Th2 cells. Thus, these results suggest that an allergic recall response to recurring Ag exposures preferentially triggers an increase of Ag-specific CD4(+) Th2 cells, which facilitates the collaborative interactions between acquired CD4(+) Th2 cells and innate ILC2s to drive the exacerbation of a murine allergic airway diseases with an eosinophilic phenotype.

SEC14-like 3 is decreased in airway ciliated cells in experimental and paediatric asthma

SEC14-like 3 is decreased in airway ciliated cells in experimental and paediatric asthma

IL-37 requires IL18Rα and SIGIRR/IL-1R8 to ameliorate experimental allergic asthma in mice

IL-37 requires IL18Rα and SIGIRR/IL-1R8 to ameliorate experimental allergic asthma in mice

Safety and tolerability of a novel inhaled GATA3 mRNA targeting DNAzyme in patients with TH2-driven asthma

Safety and tolerability of a novel inhaled GATA3 mRNA targeting DNAzyme in patients with TH2-driven asthma

Alveolar macrophages express membrane CD200 that inhibits mast cell activation

Alveolar Macrophages are central regulators of pulmonary immune responses, yet their regulatory functions are misunderstood. CD200, a transmembrane protein, and its receptor (CD200R) play a critical role in the resolution of inflammation, but their role in asthma is still unclear. CD200 is expressed on many cell types such as leukocytes, T cells, B cells, epithelial cells, and endothelial cells, while CD200R is expressed exclusively on myeloid cells including alveolar macrophages (AM) and mast cells (MC), which play a key role in asthma. Recent study showed that leukocytes from asthmatic patients express lower level of CD200 during exacerbations, suggesting a dysregulation of CD200 pathway. Thus, we investigated the modulation of CD200 expression on AM following allergen challenge and the inhibition of MC functions by AM CD200. 
 Expression of CD200 and CD200R were measured on AM from naive and sensitized rats before and after allergen challenge using flow cytometry. AM modulation of antigen‐stimulated MC was investigated in vitro using co‐culture and MC degranulation and cytokine production.
 AM from naive and sensitized rats express similar level of CD200. However, allergen exposure increased CD200 expression on AM of naïve rats (that do not develop signs of asthma), but not on AM of sensitized rats (that develop experimental asthma). No difference between groups was observed for CD200R expression. Naive AM inhibited antigen‐stimulated MC degranulation and cytokine production. The addition of neutralizing anti‐CD200R antibody abrogated AM inhibitory effects. 
 These results suggest that modulation of CD200 expression on AM could have an important role in asthma regulation.

The potential effect of the angiotensin II receptor blocker telmisartan in regulating OVA-induced airway remodeling in experimental rats.

Bronchial asthma is a true ascending clinical problem. Angiotensin II is now accused to be potentially implicated in its pathogenesis, being a potent pro-inflammatory mediator with remodeling effects. This study aims to evaluate the possible protective effect of telmisartan, an angiotensin II receptor blocker, on experimentally-induced bronchial asthma. Animals were divided into 5 groups; a normal control group, an asthma control group, a reference treatment group, receiving dexamethasone, and two treatment groups, receiving telmisartan in two dose levels. Bronchial asthma was induced by intraperitoneal sensitization followed by intranasal challenge with ovalbumin (OVA). Test agents were administered prior to each intranasal OVA challenge. Lung function tests, namely tidal volume (TV) and peak expiratory flow rate (PEF) were assessed 1h after the last challenge. One day after the last challenge, absolute eosinophil counts (AEC) in blood and bronchoalveolar lavage fluids (BALF) were assessed. Serum immunoglobulin E (IgE) as well as BALF total nitrate/nitrite (NOx) were assessed. Oxidative and inflammatory biomarkers, namely lung tissue superoxide dismutase (SOD), glutathione reduced (GSH), tumor necrosis factor-alpha (TNF-α) and interleukin-5 (IL-5), were also assessed, in addition to histopathological study. Telmisartan administration in both doses significantly improved TV, PEF, AEC, IgE, NOx, GSH, SOD, TNF-α and IL-5 values compared to asthma control values. Histopathological study strongly supported the results of biochemical estimations, particularly regarding airway remodeling. These results suggest that telmisartan may have potential protecting effects against experimental bronchial asthma, probably due to its bronchodilator, antioxidant and anti-inflammatory effects.

ILC2 and ILC3 contribute to house dust mite (HDM)-induced asthma in obese mice

Many epidemiological and clinical evidences suggest that obesity is an important risk factor for asthma, but the underlying mechanisms remain poorly understood. Besides adaptive immunity and adipokines, innate mechanisms have been involved in both diseases. Given the recent implication of group 2 innate lymphoid cells (ILC2) in asthma and adipose tissue homeostasis, and of ILC3 in obesity-associated airway hyperresponsiveness (AHR), the purpose of this study was to characterize the contribution of adaptive T helper cells versus ILC in a model of house dust mite (HDM)-induced asthma exacerbation by diet-induced obesity. Obesity was induced by a 60% high fat diet (HFD), and lean mice were fed with a low fat diet (LFD). Twelve weeks later, asthma was induced by intranasal administration of HDM. The cardinal features of experimental asthma were evaluated in combination with a flow cytometric analysis of the different adaptive or innate lymphoid population proportions and cytokine production. In lean mice, HDM induced the classical parameters of allergic asthma including increased airway hyperresponsiveness, IgE production, cell recruitment in the bronchoalveolar lavage with eosinophil, lymphocyte and neutrophil infiltrations. Histologic staining confirmed increased mucus accumulation in lungs of asthmatic mice. Feeding mice with HFD resulted in the exacerbation of some features of asthma including serum concentrations of IgE, recruitment of eosinophils in the bronchoalveolar lavage and airway hyperreactivity. Evaluation of the T cell cytokine profile in the lung protein extracts showed an exacerbation of the Th2 and Th17 profiles in obese mice compared to lean mice after HDM challenge. Moreover, the number of ILC2 and ILC3 NCR − cells was increased in HDM-challenged obese mice compared to HDM-challenged lean mice, with an increased intracellular expression of IL-13, IL-17A and IL-22. At the mRNA level, IL-33 mRNA was strongly increased in HDM-challenged obese mice as compared with HDM-challenged lean mice, suggesting that IL-33 might contribute to the induction of ILC2 in obese asthmatic mice. These results support the concept that obesity may exacerbate allergen-induced asthma by a mechanism involving in part ILC2 and ILC3.

IL-37 requires IL18Rα and SIGIRR to ameliorate experimental allergic asthma in mice

Rationale: Recently, the new cytokine interleukin (IL) 37 has been described as a negative regulator of the innate immune system. It reduces activation of DCs and the production of pro-inflammatory mediators in TLR stimulated murine and human macrophage, monocyte and epithelial cell lines. Results from the CLARA study gave the first hint towards an implication of IL-37 in asthma pathogenesis. However, until yet it is unknown, whether IL-37 plays a role in asthma pathogenesis by providing anti-inflammatory effects on an adaptive immune response and through which receptor it exerts such effects.

Treatment with a sphingosine analog after the inception of house dust mite-induced airway inflammation alleviates key features of experimental asthma

BackgroundIn vivo phosphorylation of sphingosine analogs with their ensuing binding and activation of their cell-surface sphingosine-1-phosphate receptors is regarded as the main immunomodulatory mechanism of this new class of drugs. Prophylactic treatment with sphingosine analogs interferes with experimental asthma by impeding the migration of dendritic cells to draining lymph nodes. However, whether these drugs can also alleviate allergic airway inflammation after its onset remains to be determined. Herein, we investigated to which extent and by which mechanisms the sphingosine analog AAL-R interferes with key features of asthma in a murine model during ongoing allergic inflammation induced by Dermatophagoides pteronyssinus.MethodsBALB/c mice were exposed to either D. pteronyssinus or saline, intranasally, once-daily for 10 consecutive days. Mice were treated intratracheally with either AAL-R, its pre-phosphorylated form AFD-R, or the vehicle before every allergen challenge over the last four days, i.e. after the onset of allergic airway inflammation. On day 11, airway responsiveness to methacholine was measured; inflammatory cells and cytokines were quantified in the airways; and the numbers and/or viability of T cells, B cells and dendritic cells were assessed in the lungs and draining lymph nodes.ResultsAAL-R decreased airway hyperresponsiveness induced by D. pteronyssinus by nearly 70%. This was associated with a strong reduction of IL-5 and IL-13 levels in the airways and with a decreased eosinophilic response. Notably, the lung CD4+ T cells were almost entirely eliminated by AAL-R, which concurred with enhanced apoptosis/necrosis in that cell population. This inhibition occurred in the absence of dendritic cell number modulation in draining lymph nodes. On the other hand, the pre-phosphorylated form AFD-R, which preferentially acts on cell-surface sphingosine-1-phosphate receptors, was relatively impotent at enhancing cell death, which led to a less efficient control of T cell and eosinophil responses in the lungs.ConclusionAirway delivery of the non-phosphorylated sphingosine analog, but not its pre-phosphorylated counterpart, is highly efficient at controlling the local T cell response after the onset of allergic airway inflammation. The mechanism appears to involve local induction of lymphocyte apoptosis/necrosis, while mildly affecting dendritic cell and T cell accumulation in draining lymph nodes.

Experimental Asthma Induced By Tropomyosins from Cockroach and Shrimp: Insights into in Vivo Cross-Reactivity

In vivo cross-reactivity among tropomyosins, major pan-allergens among invertebrates, is not established. Our aim was to investigate the effects of purified tropomyosins from cockroach (recombinant Pera7) and shrimp (natural Litv1) on airway inflammation and hyperresponsiveness in a mouse model of asthma. Balb/c mice, 4 to 6 weeks-old, were sensitized twice with 50μg of rPera7 or nLitv1 intraperitoneally with 1 mg alum, and challenged with 50μg of rPer7 or nLitv1 intranasally for three days. A group was sensitized with rPera7 and challenged with nLitv1 under same conditions. Controls received saline on same days. Twenty-four hours after the last challenge, mice were ventilated with FlexiVent®, and in vivo bronchial hyperresponsiveness was evaluated with inhaled methacholine (6.25,12.5,25 and 50mg/ml). After ventilation, bronchoalveolar lavage fluid (BALF) was collected and cell counts were performed. Sensitization and challenge of mice with rPera7 or nLitv1 resulted in increase in bronchial hyperresponsiveness, given by increase in resistance and elastance. Total cells in BALF increased in rPera7 and nLitv1 groups, as compared to controls. There was increase in macrophages (5x104 vs 1x105 and 3x105 for rPera7 and nLitv1, p<0.001) and eosinophils (2x103 vs 1.4x105 and 9.1x105, p<0.001). Mice immunized with rPera7 and challenged with nLitv1 showed no changes in bronchial hyperresponsiveness or cells on BALF as compared to controls. Experimental asthma induced by tropomyosins from cockroach and shrimp mimicked the main characteristics of human asthma. Despite the high degree of sequence identity and IgE immunologic cross-reactivity, our data suggested that in vivo cross-reactivity of these tropomyosins is unlikely.

IL-37 requires IL-18Rα and SIGIRR/IL-1R8 to diminish allergic airway inflammation in mice.

Interleukin (IL) 37 has been described as a negative regulator of innate immunity, as it reduces the activation and cytokine production of different innate immune cells. Recently, results from the CLARA childhood asthma cohort suggested an implication of IL-37 for human asthma pathogenesis. This study aimed to investigate the effects of IL-37 on allergic airway inflammation in a mouse model of experimental asthma. Peripheral blood mononuclear cells (PBMCs) of children were cultured for 48h (anti-CD3/anti-CD28 stimulation or unstimulated), and IL-37 concentrations in supernatants were determined. Wild-type, IL-18Rα-deficient ((-/-) ), and SIGIRR(-/-) C57BL/6 mice were sensitized to ovalbumin (OVA) and challenged with OVA aerosol to induce acute experimental asthma, and IL-37 was applied intranasally prior to each OVA challenge. Airway hyper-responsiveness (AHR), airway inflammation, cytokine levels in broncho-alveolar lavage fluid, and mucus production were determined. IL-37 production of human PBMCs was significantly lower in allergic asthmatics vs healthy children. In wild-type mice, intranasal administration of IL-37 ablated allergic airway inflammation as well as cytokine production and subsequently diminished the hallmarks of experimental asthma including mucus hyperproduction and AHR. In contrast, local application of IL-37 produced none of these effects in mice lacking either IL18Rα or SIGIRR/IL-1R8. This study demonstrates that IL-37 is able to ablate a TH2 cell-directed allergic inflammatory response and the hallmarks of experimental asthma in mice, suggesting that IL-37 may be critical for asthma pathogenesis. Furthermore, these data suggest a mode of action of IL-37 that involves IL18Rα as well as the orphan receptor SIGIRR/IL-1R8.

The histamine H4 -receptor (H4 R) regulates eosinophilic inflammation in ovalbumin-induced experimental allergic asthma in mice.

Via the histamine H4 -receptor (H4 R), histamine promotes the pathogenesis of experimental allergic asthma in mice. Application of H4 R antagonists during sensitization as well as during provocation reduces the severity of the disease. However, the specific cell types functionally expressing H4 R in experimental allergic asthma have not been well characterized in vivo. In this study, we identified the cell type(s) responsible for H4 R activity in experimental asthma and related physiological mechanisms. Using H4 R-deficient mice, we studied the role of H4 R in the sensitization and effector phase. DCs lacking H4 R expression during the in vitro sensitization reaction resulted in effector T cells unable to induce an entire eosinophilic inflammation in the lung upon adoptive transfer in vivo. Recipient mice lacking H4 R expression, which were adoptively transferred with H4 R(+/+) T cells polarized in the presence of H4 R(+/+) DCs, showed reduced signs of inflammation and ameliorated lung function. Here, we provide in vivo evidence that in experimental asthma in mice the H4 R specifically regulates activation of DCs during sensitization, while in the effector phase the H4 R is active in cells involved in the activation of eosinophils, and possibly other cells. A putative therapy targeting the H4 R may be an option for asthma patients developing IL-5-dependent eosinophilia.

Acupuncture Attenuated Inflammation and Inhibited Th17 and Treg Activity in Experimental Asthma.

Acupuncture is an effective therapeutic method in asthma treatment in traditional Chinese medicine. Here, we evaluated the effect of acupuncture on airway hyperresponsiveness (AHR) and the associated inflammatory changes as well as Th17 and Treg activity in ovalbumin- (OVA-) induced experimental asthma. Our results revealed that acupuncture treatment significantly inhibited AHR, lung inflammation, and mucus secretion of experimental asthma mice. Furthermore, a decrease in lymphocytes and eosinophils as well as neutrophils was observed in bronchoalveolar lavage fluid (BALF) of mice treated with acupuncture. Acupuncture reduced the OVA specific IgE level as well as the Th17 cytokine levels including IL-17A, IL-17F, and IL-22 in the serum of the experimental asthma mice. Acupuncture treatment group also had reduced CD4+IL-17A+ cell numbers and increased CD4+Foxp3+ cell numbers in BALF. In addition, acupuncture could inhibit IL-17R, RORγt, p65, and the inhibitor of NF-κB kinase-α (IKKα) protein expression. Our results indicated that acupuncture was effective in inhibiting AHR and inflammation in OVA-induced experimental asthma, which may be associated with the regulation of Th17 and Treg activity and NF-κB pathway.

Inhaled and systemic glucocorticoids reduce regulatory T cells numbers in a HDM-model of allergy

Event Abstract Back to Event Inhaled and systemic glucocorticoids reduce regulatory T cells numbers in a HDM-model of allergy Jamil Z. Kitoko1, 2*, Tatiana Paula T. Ferreira3, Carolina T. De Azevedo3, Ana Carolina S. De Arantes3, Marco A. Martins3 and Priscilla C. Olsen2, 3 1 Federal University of Rio de Janeiro, Carlos Chagas Filho Institute of Biophysics, Brazil 2 Federal University of Rio de Janeiro, School of Pharmacy, Brazil 3 Oswaldo Cruz Foundation/IOC, Brazil Introduction: Glucocorticoids (GCs) are the main anti-inflammatory compounds used to treat asthma. Several studies suggest that GCs may act by increasing the number and activity of regulatory T (Treg) cells, with subsequent upregulation of IL-10 production. Nevertheless, recent data have shown that GCs can negatively impact the levels of these anti-inflammatory cells. The aim of this study was to clarify the effect of treatment with GCs on Treg cells in experimental asthma. Methods and Results: AJ mice were intranasally challenged with house dust mite (HDM) extract 3 times a week, for 3 weeks. Treatments were performed during the last week of challenge with either nebulized budesonide (bude) or oral dexamethasone (dexa). Analyses were performed 24 h after the last challenge. Broncoalveolar lavage fluid (BALF) analyses showed that dexa reduced leukocyte infiltration (11.07 x105 ± 2.33, n=7), including eosinophil infiltration (4.53 x105 ± 1.55, n=7), both generated by HDM exposure (respectively, 23.71 ± 5.38 and 13.75 ± 3.66 (x105), n=7). Flow cytometry analyses reveals elevated numbers of CD4+CD25+Foxp3+ cells in BALF of mice challenged with HDM (6527 ± 1047, n=6), which were decreased by dexa or bude treatment (respectively, 1817 ± 424.1 and 2824 ± 486.1, n=6). Dexa or bude reduced cellularity (respectively, 3500 ± 471.4 and 9150 ± 1553 (x103), n=9) as well as values of CD4+CD25+Foxp3+ cells (respectively, 67060 ± 6851 and 88670 ± 8568, n=6) in thymus, compared to control groups. By ELISA, elevated numbers of IL-10 were detected in lung of HDM-group mice (432.7 ± 15.4, n=10), while dexa or bude treatment did not altered these values (respectively, 388.3 ± 30.52, n=9 and 451.1 ± 19.76, n=10). All group data are presented as mean ± SEM. License of FIOCRUZ’s Ethics Committee on Use of Laboratory Animals approval is LW-23/10. Conclusion: These data suggest that treatment with GCs reduces lung number of Treg cells in asthma, independently of the route of administration, probably by reducing thymic production of T cells. Acknowledgements CNPq, FAPERJ Keywords: Asthma, Glucocorticoids, Treg cells, Thymus Gland, HDM allergens Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015. Presentation Type: Poster Presentation Topic: Immunotherapy Citation: Kitoko JZ, Ferreira TT, De Azevedo CT, De Arantes AS, Martins MA and Olsen PC (2015). Inhaled and systemic glucocorticoids reduce regulatory T cells numbers in a HDM-model of allergy. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00274 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 15 Apr 2015; Published Online: 14 Sep 2015. * Correspondence: Mr. Jamil Z Kitoko, Federal University of Rio de Janeiro, Carlos Chagas Filho Institute of Biophysics, Rio de Janeiro, Brazil, jamilkitoko@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Jamil Z Kitoko Tatiana Paula T Ferreira Carolina T De Azevedo Ana Carolina S De Arantes Marco A Martins Priscilla C Olsen Google Jamil Z Kitoko Tatiana Paula T Ferreira Carolina T De Azevedo Ana Carolina S De Arantes Marco A Martins Priscilla C Olsen Google Scholar Jamil Z Kitoko Tatiana Paula T Ferreira Carolina T De Azevedo Ana Carolina S De Arantes Marco A Martins Priscilla C Olsen PubMed Jamil Z Kitoko Tatiana Paula T Ferreira Carolina T De Azevedo Ana Carolina S De Arantes Marco A Martins Priscilla C Olsen Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

AT-RvD1 modulates CCL-2 and CXCL-8 production and NF-κB, STAT-6, SOCS1, and SOCS3 expression on bronchial epithelial cells stimulated with IL-4.

Bronchial epithelial cells represent the first line of defense against microorganisms and allergens in the airways and play an important role in chronic inflammatory processes such as asthma. In an experimental model, both RvD1 and AT-RvD1, lipid mediators of inflammation resolution, ameliorated some of the most important phenotypes of experimental asthma. Here, we extend these results and demonstrate the effect of AT-RvD1 on bronchial epithelial cells (BEAS-2B) stimulated with IL-4. AT-RvD1 (100 nM) decreased both CCL2 and CXCL-8 production, in part by decreasing STAT6 and NF-κB pathways. Furthermore, the effects of AT-RvD1 were ALX/FRP2 receptor dependent, as the antagonist of this receptor (BOC1) reversed the inhibition of these chemokines by AT-RvD1. In addition, AT-RvD1 decreased SOCS1 and increased SOCS3 expression, which play important roles in Th1 and Th17 modulation, respectively. In conclusion, AT-RvD1 demonstrated significant effects on the IL-4-induced activation of bronchial epithelial cells and consequently the potential to modulate neutrophilic and eosinophilic airway inflammation in asthma. Taken together, these findings identify AT-RvD1 as a potential proresolving therapeutic agent for allergic responses in the airways.

Microbiome and Asthma: What Have Experimental Models Already Taught Us?

Asthma is a chronic inflammatory disease that imposes a substantial burden on patients, their families, and the community. Although many aspects of the pathogenesis of classical allergic asthma are well known by the scientific community, other points are not yet understood. Experimental asthma models, particularly murine models, have been used for over 100 years in order to better understand the immunopathology of asthma. It has been shown that human microbiome is an important component in the development of the immune system. Furthermore, the occurrence of many inflammatory diseases is influenced by the presence of microbes. Again, experimental models of asthma have helped researchers to understand the relationship between the microbiome and respiratory inflammation. In this review, we discuss the evolution of murine models of asthma and approach the major studies involving the microbiome and asthma.