Browse
Submit Data
Databases
API
Help

Dataset Information

46 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Immunoproteasome Inhibition Reduces the T Helper 2 Response in Mouse Models of Allergic Airway Inflammation.

ABSTRACT:

Background

Allergic asthma is a chronic disease and medical treatment often fails to fully control the disease in the long term, leading to a great need for new therapeutic approaches. Immunoproteasome inhibition impairs T helper cell function and is effective in many (auto-) inflammatory settings but its effect on allergic airway inflammation is unknown.

Methods

Immunoproteasome expression was analyzed in in vitro polarized T helper cell subsets. To study Th2 cells in vivo acute allergic airway inflammation was induced in GATIR (GATA-3-vYFP reporter) mice using ovalbumin and house dust mite extract. Mice were treated with the immunoproteasome inhibitor ONX 0914 or vehicle during the challenge phase and the induction of airway inflammation was analyzed.

Results

In vitro polarized T helper cell subsets (Th1, Th2, Th17, and Treg) express high levels of immunoproteasome subunits. GATIR mice proved to be a useful tool for identification of Th2 cells. Immunoproteasome inhibition reduced the Th2 response in both airway inflammation models. Furthermore, T cell activation and antigen-specific cytokine secretion was impaired and a reduced infiltration of eosinophils and professional antigen-presenting cells into the lung and the bronchoalveolar space was observed in the ovalbumin model.

Conclusion

These results show the importance of the immunoproteasome in Th2 cells and airway inflammation. Our data provides first insight into the potential of using immunoproteasome inhibition to target the aberrant Th2 response, e.g. in allergic airway inflammation.

SUBMITTER: Oliveri F

PROVIDER: S-EPMC9197384 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Silencing Nociceptor Neurons Reduces Allergic Airway Inflammation.

Project description:Lung nociceptors initiate cough and bronchoconstriction. To elucidate if these fibers also contribute to allergic airway inflammation, we stimulated lung nociceptors with capsaicin and observed increased neuropeptide release and immune cell infiltration. In contrast, ablating Nav1.8(+) sensory neurons or silencing them with QX-314, a charged sodium channel inhibitor that enters via large-pore ion channels to specifically block nociceptors, substantially reduced ovalbumin- or house-dust-mite-induced airway inflammation and bronchial hyperresponsiveness. We also discovered that IL-5, a cytokine produced by activated immune cells, acts directly on nociceptors to induce the release of vasoactive intestinal peptide (VIP). VIP then stimulates CD4(+) and resident innate lymphoid type 2 cells, creating an inflammatory signaling loop that promotes allergic inflammation. Our results indicate that nociceptors amplify pathological adaptive immune responses and that silencing these neurons with QX-314 interrupts this neuro-immune interplay, revealing a potential new therapeutic strategy for asthma.

| S-EPMC4506220 | biostudies-literature

Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation.

Project description:Rhinoviruses cause serious morbidity and mortality as the major etiological agents of asthma exacerbations and the common cold. A major obstacle to understanding disease pathogenesis and to the development of effective therapies has been the lack of a small-animal model for rhinovirus infection. Of the 100 known rhinovirus serotypes, 90% (the major group) use human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor and do not bind mouse ICAM-1; the remaining 10% (the minor group) use a member of the low-density lipoprotein receptor family and can bind the mouse counterpart. Here we describe three novel mouse models of rhinovirus infection: minor-group rhinovirus infection of BALB/c mice, major-group rhinovirus infection of transgenic BALB/c mice expressing a mouse-human ICAM-1 chimera and rhinovirus-induced exacerbation of allergic airway inflammation. These models have features similar to those observed in rhinovirus infection in humans, including augmentation of allergic airway inflammation, and will be useful in the development of future therapies for colds and asthma exacerbations.

| S-EPMC3384678 | biostudies-literature

Systemic Pharmacological Smoothened Inhibition Reduces Lung T-Cell Infiltration and Ameliorates Th2 Inflammation in a Mouse Model of Allergic Airway Disease.

Project description:Allergic asthma is a common inflammatory airway disease in which Th2 immune response and inflammation are thought to be triggered by inhalation of environmental allergens. Many studies using mouse models and human tissues and genome-wide association have indicated that Sonic Hedgehog (Shh) and the Hedgehog (Hh) signaling pathway are involved in allergic asthma and that Shh is upregulated in the lung on disease induction. We used a papain-induced mouse model of allergic airway inflammation to investigate the impact of systemic pharmacological inhibition of the Hh signal transduction molecule smoothened on allergic airway disease induction and severity. Smoothened-inhibitor treatment reduced the induction of Shh, IL-4, and IL-13 in the lung and decreased serum IgE, as well as the expression of Smo, Il4, Il13, and the mucin gene Muc5ac in lung tissue. Smoothened inhibitor treatment reduced cellular infiltration of eosinophils, mast cells, basophils, and CD4+ T-cells to the lung, and eosinophils and CD4+ T-cells in the bronchoalveolar lavage. In the mediastinal lymph nodes, smoothened inhibitor treatment reduced the number of CD4+ T-cells, and the cell surface expression of Th2 markers ST2 and IL-4rα and expression of Th2 cytokines. Thus, overall pharmacological smoothened inhibition attenuated T-cell infiltration to the lung and Th2 function and reduced disease severity and inflammation in the airway.

| S-EPMC8463265 | biostudies-literature

Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation.

Project description:Eosinophils are multifunctional leukocytes that degrade and remodel tissue extracellular matrix through production of proteolytic enzymes, release of proinflammatory factors to initiate and propagate inflammatory responses, and direct activation of mucus secretion and smooth muscle cell constriction. Thus, eosinophils are central effector cells during allergic airway inflammation and an important clinical therapeutic target. Here we describe the use of an injectable MMP-targeted optical sensor that specifically and quantitatively resolves eosinophil activity in the lungs of mice with experimental allergic airway inflammation. Through the use of real-time molecular imaging methods, we report the visualization of eosinophil responses in vivo and at different scales. Eosinophil responses were seen at single-cell resolution in conducting airways using near-infrared fluorescence fiberoptic bronchoscopy, in lung parenchyma using intravital microscopy, and in the whole body using fluorescence-mediated molecular tomography. Using these real-time imaging methods, we confirmed the immunosuppressive effects of the glucocorticoid drug dexamethasone in the mouse model of allergic airway inflammation and identified a viridin-derived prodrug that potently inhibited the accumulation and enzyme activity of eosinophils in the lungs. The combination of sensitive enzyme-targeted sensors with noninvasive molecular imaging approaches permitted evaluation of airway inflammation severity and was used as a model to rapidly screen for new drug effects. Both fluorescence-mediated tomography and fiberoptic bronchoscopy techniques have the potential to be translated into the clinic.

| S-EPMC2579705 | biostudies-literature

Winter Exercise Reduces Allergic Airway Inflammation: A Randomized Controlled Study.

Project description:Background: Physical exercise is often recommended as additional treatment for people suffering from allergic rhinitis and/or asthma, but less is known about the specific effects of recreational winter outdoor exercise on allergic airway inflammation. Methods: We performed a longitudinal, randomized controlled intervention study to investigate the effects of recreational winter exercise on allergic airway inflammation, quality of life, spirometry and cardiorespiratory fitness in adults suffering from allergic rhinitis and/or asthma. The exercise group participated in a ten-day winter sports program. The control group did not receive any intervention. Results: A significant improvement of fractional oral exhaled nitric oxide (FeNO; p = 0.008, day 10) and a significant decrease in FeNO after a single 4 h hiking tour (p < 0.001, time effect) were observed for the exercise group. The nasal eosinophilic cell count revealed a short-term reduction (p = 0.021, treatment effect) in the exercise group and for the visual analogue scale sustainable improvements in allergic symptoms (p < 0.001, day 60) were found. No adverse effects of outdoor winter exercise were observed. Conclusion: Recreational winter exercise at moderately cold temperatures reduces allergic airway inflammation measured as FeNO, nasal eosinophilic cell count and induces sustainable improvements in allergic symptoms.

| S-EPMC6603979 | biostudies-literature

Mouse models to unravel the role of inhaled pollutants on allergic sensitization and airway inflammation.

Project description:Air pollutant exposure has been linked to a rise in wheezing illnesses. Clinical data highlight that exposure to mainstream tobacco smoke (MS) and environmental tobacco smoke (ETS) as well as exposure to diesel exhaust particles (DEP) could promote allergic sensitization or aggravate symptoms of asthma, suggesting a role for these inhaled pollutants in the pathogenesis of asthma. Mouse models are a valuable tool to study the potential effects of these pollutants in the pathogenesis of asthma, with the opportunity to investigate their impact during processes leading to sensitization, acute inflammation and chronic disease. Mice allow us to perform mechanistic studies and to evaluate the importance of specific cell types in asthma pathogenesis. In this review, the major clinical effects of tobacco smoke and diesel exhaust exposure regarding to asthma development and progression are described. Clinical data are compared with findings from murine models of asthma and inhalable pollutant exposure. Moreover, the potential mechanisms by which both pollutants could aggravate asthma are discussed.

| S-EPMC2831838 | biostudies-literature

Control of T helper 2 cell function and allergic airway inflammation by PKCzeta.

Project description:Asthma is a disease of chronic airway inflammation in which T helper (Th) 2 cells play a critical role. The molecular mechanisms controlling Th2 differentiation and function are of paramount importance in biology and immunology. PKCzeta has been implicated in the regulation of apoptosis and NF-kappaB, as well as in the control of T-dependent responses, although no defects were detected in naïve T cells from PKCzeta-/- mice. Here, we report that PKCzeta is critical for IL-4 signaling and Th2 differentiation. Thus, PKCzeta levels are increased during Th2 differentiation, but not Th1 differentiation, of CD4+ T cells, and the loss of PKCzeta impairs the secretion of Th2 cytokines in vitro and in vivo, as well as the nuclear translocation and tyrosine phosphorylation of Stat6 and Jak1 activation, essential downstream targets of IL-4 signaling. Moreover, PKCzeta-/- mice display dramatic inhibition of ovalbumin-induced allergic airway disease, strongly suggesting that PKCzeta can be a therapeutic target in asthma.

| S-EPMC1174981 | biostudies-literature

IFITM proteins drive type 2 T helper cell differentiation and exacerbate allergic airway inflammation.

Project description:The interferon-inducible transmembrane (Ifitm/Fragilis) genes encode homologous proteins that are induced by IFNs. Here, we show that IFITM proteins regulate murine CD4+ Th cell differentiation. Ifitm2 and Ifitm3 are expressed in wild-type (WT) CD4+ T cells. On activation, Ifitm3 was downregulated and Ifitm2 was upregulated. Resting Ifitm-family-deficient CD4+ T cells had higher expression of Th1-associated genes than WT and purified naive Ifitm-family-deficient CD4+ T cells differentiated more efficiently to Th1, whereas Th2 differentiation was inhibited. Ifitm-family-deficient mice, but not Ifitm3-deficient mice, were less susceptible than WT to induction of allergic airways disease, with a weaker Th2 response and less severe disease and lower Il4 but higher Ifng expression and IL-27 secretion. Thus, the Ifitm family is important in adaptive immunity, influencing Th1/Th2 polarization, and Th2 immunopathology.

| S-EPMC6396086 | biostudies-literature

Interaction of Interleukin-17A with a Th2 Response in a Mouse Model of Allergic Airway Inflammation.

Project description:BackgroundA total of 262 million people worldwide suffer from asthma and 461000 people died from it in 2019. Asthma is a disease with different endotypes defined by the granulocytes found in the asthmatic lung. In allergic asthma, the eosinophilic endotype is present, driven by a TH2 response. A TH17 immune response leads to the neutrophil endotype. This often causes uncontrolled asthma and is triggered by pollutants, microbes, and oxidative stress. It has been described that a significant number of patients with eosinophilic asthma develop mixed granulocytic asthma over time. The severity of asthma in the mixed endotype is related to the proportion of neutrophils in the lungs.PurposeIn this report, we address the question of how a TH2 response interacts with IL-17A in allergic asthma.MethodsTo this end, we used a mouse model to induce allergic asthma followed by an aerosol challenge with ovalbumin. To investigate the role of IL-17A, we administered IL-17A intranasally during the challenge phase.ResultsIL-17A alone did not elicit an immune response, whereas in combination with allergic asthma, it resulted in a shift of the asthmatic endotype from eosinophilic to neutrophilic. TGFβ1 was increased in these lungs compared to asthmatic lungs without IL-17A, as was the expression of the IL-17A receptor subunits IL-17RA and IL-17RC. In cultures with human cells, we also found that IL-17A increased the expression of its receptors only in combination with IL-13. We also found this effect for IL-8, which attracts neutrophils in humans.ConclusionsThe TH2 response increased the sensitivity to IL-17A in a mouse asthma model as well as in human cell lines.

| S-EPMC10340318 | biostudies-literature

PDE3 Inhibition Reduces Epithelial Mast Cell Numbers in Allergic Airway Inflammation and Attenuates Degranulation of Basophils and Mast Cells.

Project description:Epithelial mast cells are generally present in the airways of patients with allergic asthma that are inadequately controlled. Airway mast cells (MCs) are critically involved in allergic airway inflammation and contribute directly to the main symptoms of allergic patients. Phosphodiesterase 3 (PDE3) tailors signaling of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are critical intracellular second messenger molecules in various signaling pathways. This paper investigates the pathophysiological role and disease-modifying effects of PDE3 in mouse bone marrow-derived MCs (bmMCs), human LAD2- and HMC1 mast cell lines, human blood basophils, and peripheral blood-derived primary human MCs (HuMCs). In a chronic house dust mite (HDM)-driven allergic airway inflammation mouse model, we observed that PDE3 deficiency or PDE3 inhibition (PDE3i) therapy reduced the numbers of epithelial MCs, when compared to control mice. Mouse bone marrow-derived MCs (bmMCs) and the human HMC1 and LAD2 cell lines predominantly expressed PDE3B and PDE4A. BmMCs from Pde3-/- mice showed reduced loss of the degranulation marker CD107b compared with wild-type BmMCs, when stimulated in an immunoglobulin E (IgE)-dependent manner. Following both IgE-mediated and substance P-mediated activation, PDE3i-pretreated basophils, LAD2 cells, and HuMCs, showed less degranulation than diluent controls, as measured by surface CD63 expression. MCs lacking PDE3 or treated with the PDE3i enoximone exhibited a lower calcium flux upon stimulation with ionomycine. In conclusion PDE3 plays a critical role in basophil and mast cell degranulation and therefore its inhibition may be a treatment option in allergic disease.

| S-EPMC7206980 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data