scholarly journals Inhibition of β-Catenin/CREB Binding Protein Signaling Attenuates House Dust Mite-Induced Goblet Cell Metaplasia in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Virinchi N. S. Kuchibhotla ◽  
Malcolm R. Starkey ◽  
Andrew T. Reid ◽  
Irene H. Heijink ◽  
Martijn C. Nawijn ◽  
...  
Keyword(s):  
Goblet Cell ◽  
House Dust ◽  
House Dust Mite ◽  
Binding Protein ◽  
Periodic Acid ◽  
Creb Binding Protein ◽  
Mucus Production ◽  
Dust Mite ◽  
Epithelial Junctions ◽  
Goblet Cell Metaplasia

Excessive mucus production is a major feature of allergic asthma. Disruption of epithelial junctions by allergens such as house dust mite (HDM) results in the activation of β-catenin signaling, which has been reported to stimulate goblet cell differentiation. β-catenin interacts with various co-activators including CREB binding protein (CBP) and p300, thereby regulating the expression of genes involved in cell proliferation and differentiation, respectively. We specifically investigated the role of the β-catenin/CBP signaling pathway in goblet cell metaplasia in a HDM-induced allergic airway disease model in mice using ICG-001, a small molecule inhibitor that blocks the binding of CBP to β-catenin. Female 6- 8-week-old BALB/c mice were sensitized to HDM/saline on days 0, 1, and 2, followed by intranasal challenge with HDM/saline with or without subcutaneous ICG-001/vehicle treatment from days 14 to 17, and samples harvested 24 h after the last challenge/treatment. Differential inflammatory cells in bronchoalveolar lavage (BAL) fluid were enumerated. Alcian blue (AB)/Periodic acid–Schiff (PAS) staining was used to identify goblet cells/mucus production, and airway hyperresponsiveness (AHR) was assessed using invasive plethysmography. Exposure to HDM induced airway inflammation, goblet cell metaplasia and increased AHR, with increased airway resistance in response to the non-specific spasmogen methacholine. Inhibition of the β-catenin/CBP pathway using treatment with ICG-001 significantly attenuated the HDM-induced goblet cell metaplasia and infiltration of macrophages, but had no effect on eosinophils, neutrophils, lymphocytes or AHR. Increased β-catenin/CBP signaling may promote HDM-induced goblet cell metaplasia in mice.

scholarly journals PI3Kδ Inhibition Prevents IL33, ILC2s and Inflammatory Eosinophils in Persistent Airway Inflammation

2021 ◽  
Author(s):  
Sorif Uddin ◽  
Augustin Amour ◽  
David J Lewis ◽  
Chris D Edwards ◽  
Matthew G Williamson ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Goblet Cell ◽  
House Dust ◽  
House Dust Mite ◽  
Inflammatory Responses ◽  
Lymphoid Cells ◽  
Antibody Treatment ◽  
Dust Mite ◽  
Group 2 ◽  
Goblet Cell Metaplasia

Abstract Background: Phosphoinositide-3-kinase-delta (PI3Kδ) inhibition is a promising therapeutic approach for inflammatory conditions due to its role in leucocyte proliferation, migration and activation. However, the effect of PI3Kδ inhibition on group-2-innate lymphoid cells (ILC2s) and inflammatory eosinophils remains unknown. Using a murine model exhibiting persistent airway inflammation we sought to understand the effect of PI3Kδ inhibition, montelukast and anti-IL5 antibody treatment on IL33 expression, group-2-innate lymphoid cells, inflammatory eosinophils, and goblet cell metaplasia. Results: Mice were sensitised to house dust mite and after allowing inflammation to resolve, were re-challenged with house dust mite to re-initiate airway inflammation. ILC2s were found to persist in the airways following house dust mite sensitisation and after re-challenge their numbers increased further along with accumulation of inflammatory eosinophils. In contrast to montelukast or anti-IL5 antibody treatment, PI3Kδ inhibition ablated IL33 expression and prevented group-2-innate lymphoid cell accumulation. Only PI3Kδ inhibition and IL5 neutralization reduced the infiltration of inflammatory eosinophils. Moreover, PI3Kδ inhibition reduced goblet cell metaplasia. Conclusions: Hence, we show that PI3Kδ inhibition dampens allergic inflammatory responses by ablating key cell types and cytokines involved in T-helper-2-driven inflammatory responses.

scholarly journals PI3Kδ inhibition prevents IL33, ILC2s and inflammatory eosinophils in persistent airway inflammation

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Sorif Uddin ◽  
Augustin Amour ◽  
David J. Lewis ◽  
Chris D. Edwards ◽  
Matthew G. Williamson ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Goblet Cell ◽  
House Dust ◽  
House Dust Mite ◽  
Inflammatory Responses ◽  
Lymphoid Cells ◽  
Antibody Treatment ◽  
Dust Mite ◽  
Group 2 ◽  
Goblet Cell Metaplasia

Abstract Background Phosphoinositide-3-kinase-delta (PI3Kδ) inhibition is a promising therapeutic approach for inflammatory conditions due to its role in leucocyte proliferation, migration and activation. However, the effect of PI3Kδ inhibition on group 2 innate lymphoid cells (ILC2s) and inflammatory eosinophils remains unknown. Using a murine model exhibiting persistent airway inflammation we sought to understand the effect of PI3Kδ inhibition, montelukast and anti-IL5 antibody treatment on IL33 expression, group-2-innate lymphoid cells, inflammatory eosinophils, and goblet cell metaplasia. Results Mice were sensitised to house dust mite and after allowing inflammation to resolve, were re-challenged with house dust mite to re-initiate airway inflammation. ILC2s were found to persist in the airways following house dust mite sensitisation and after re-challenge their numbers increased further along with accumulation of inflammatory eosinophils. In contrast to montelukast or anti-IL5 antibody treatment, PI3Kδ inhibition ablated IL33 expression and prevented group-2-innate lymphoid cell accumulation. Only PI3Kδ inhibition and IL5 neutralization reduced the infiltration of inflammatory eosinophils. Moreover, PI3Kδ inhibition reduced goblet cell metaplasia. Conclusions Hence, we show that PI3Kδ inhibition dampens allergic inflammatory responses by ablating key cell types and cytokines involved in T-helper-2-driven inflammatory responses.

scholarly journals Kininogen deficiency or depletion reduces enhanced pause independent of pulmonary inflammation in a house dust mite-induced murine asthma model

2019 ◽  
Vol 316 (1) ◽  
pp. L187-L196 ◽  
Author(s):  
Jack Yang ◽  
Cornelis van ’t Veer ◽  
Joris J. T. H. Roelofs ◽  
Jeroen W. J. van Heijst ◽  
Alex F. de Vos ◽  
...  
Keyword(s):  
House Dust ◽  
House Dust Mite ◽  
Lung Inflammation ◽  
Lung Pathology ◽  
Kinin System ◽  
Mucus Production ◽  
Asthma Model ◽  
Allergic Lung Inflammation ◽  
Dust Mite ◽  
Murine Asthma Model

High-molecular-weight kininogen is an important substrate of the kallikrein-kinin system. Activation of this system has been associated with aggravation of hallmark features in asthma. We aimed to determine the role of kininogen in enhanced pause (Penh) measurements and lung inflammation in a house dust mite (HDM)-induced murine asthma model. Normal wild-type mice and mice with a genetic deficiency of kininogen were subjected to repeated HDM exposure (sensitization on days 0, 1, and 2; challenge on days 14, 15, 18, and 19) via the airways to induce allergic lung inflammation. Alternatively, kininogen was depleted after HDM sensitization by twice-weekly injections of a specific antisense oligonucleotide (kininogen ASO) starting at day 3. In kininogen-deficient mice HDM induced in Penh was completely prevented. Remarkably, kininogen deficiency did not modify HDM-induced eosinophil/neutrophil influx, T helper 2 responses, mucus production, or lung pathology. kininogen ASO treatment started after HDM sensitization reduced plasma kininogen levels by 75% and reproduced the phenotype of kininogen deficiency: kininogen ASO administration prevented the HDM-induced increase in Penh without influencing leukocyte influx, Th2 responses, mucus production, or lung pathology. This study suggests that kininogen could contribute to HDM-induced rise in Penh independently of allergic lung inflammation. Further research is warranted to confirm these data using invasive measurements of airway responsiveness.

scholarly journals Insights Into Mucosal Innate Immune Responses in House Dust Mite-Mediated Allergic Asthma

2020 ◽  
Vol 11 ◽  
Author(s):  
Arwa Abu Khweek ◽  
Eunsoo Kim ◽  
Marisa R. Joldrichsen ◽  
Amal O. Amer ◽  
Prosper N. Boyaka
Keyword(s):  
Innate Immunity ◽  
Allergic Asthma ◽  
Adaptive Immunity ◽  
House Dust ◽  
House Dust Mite ◽  
Inflammatory Diseases ◽  
Allergic Sensitization ◽  
Dermatophagoides Pteronyssinus ◽  
Mucus Production ◽  
Dust Mite

The prevalence of asthma has been rising steadily for several decades, and continues to be a major public health and global economic burden due to both direct and indirect costs. Asthma is defined as chronic heterogeneous inflammatory diseases characterized by airway obstruction, mucus production and bronchospasm. Different endotypes of asthma are being recognized based on the distinct pathophysiology, genetic predisposition, age, prognosis, and response to remedies. Mucosal innate response to environmental triggers such as pollen, cigarette smoke, fragrances, viral infection, and house dust mite (HDM) are now recognized to play an important role in allergic asthma. HDM are the most pervasive allergens that co-habitat with us, as they are ubiquitous in-house dusts, mattress and bedsheets, and feed on a diet of exfoliated human skin flakes. Dermatophagoides pteronyssinus, is one among several HDM identified up to date. During the last decade, extensive studies have been fundamental in elucidating the interactions between HDM allergens, the host immune systems and airways. Moreover, the paradigm in the field of HDM-mediated allergy has been shifted away from being solely a Th2-geared to a complex response orchestrated via extensive crosstalk between the epithelium, professional antigen presenting cells (APCs) and components of the adaptive immunity. In fact, HDM have several lessons to teach us about their allergenicity, the complex interactions that stimulate innate immunity in initiating and perpetuating the lung inflammation. Herein, we review main allergens of Dermatophagoides pteronyssinus and their interactions with immunological sentinels that promote allergic sensitization and activation of innate immunity, which is critical for the development of the Th2 biased adaptive immunity to HDM allergens and development of allergic asthma.

Heterogeneous proteolytic specificity and activity of the house dust mite proteinase allergen Der p I

1997 ◽  
Vol 27 (2) ◽  
pp. 202-207 ◽  
Author(s):  
C. R. A. HEWITT ◽  
H. HORTON ◽  
R. M. JONES ◽  
D. I. PRITCHARD
Keyword(s):  
House Dust ◽  
House Dust Mite ◽  
Dust Mite

Characterization of lipophilic house dust mite-allergens with regard to the allergic phenotype

Pneumologie ◽  
2014 ◽  
Vol 68 (06) ◽  
Author(s):  
S Kull ◽  
A Petersen ◽  
S Vrtala ◽  
U Jappe
Keyword(s):  
House Dust ◽  
House Dust Mite ◽  
Dust Mite
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