New aspects of allergic mechanisms and innate immunity in asthma. Alarmins as upstream mediators of asthma inflammation.
Author
Summary, in English
The aim of this PhD thesis is to investigate the innate immune response of bronchial epithelial and smooth muscle cells to aeroallergens, allergic mediators, RV-infections alone and/or in combinations. We employed in vitro cultures of cell lines or primary human bronchial epithelial cells (HBECs) or bronchial smooth muscle cells (BSMCs) from healthy and asthmatic patients to study the regulation and molecular mechanisms of alarmins, anti-viral proteins and pro-inflammatory cytokines.
In summary, our results demonstrated that, HBECs release ATP and the pro-inflammatory cytokine IL-8, in response to stimulation with four different allergens; house dust mite (HDM), Altenaria alternata (Mugwort), Betula pendula (Birch) and Artemisia vulagris (Fungal). Only HDM induced uric acid release in HBECs as well as in our HDM-induced mouse model of allergic airway inflammation. Using specific inhibitors, we found that these responses were mainly dependent on allergen serine proteases. We further stimulated HBECs with the mast cell proteases tryptase and chymase and the results showed that these proteases induced ATP, IL-8 and IL-6 release and pre-treatment with tryptase and chymase reduced viral-induced IFN-β response. Reduced anti-viral response was associated with decreased pattern recognition receptors expression in HBECs. Further we confirmed that mast cell proteases can influence the epithelial integrity by reducing expression of tight junctional proteins expression. Next, we have investigated RV-induced IL-33 expression and regulating mechanisms in BSMCs from healthy and patients with asthma. Our results suggest that RV-induced IL-33 expression was higher in non-severe asthmatics compared to healthy and severe asthmatics. This response was mainly regulated through TLR-3 and activation of downstream signalling pathway TAK1 in BSMCs. We further show in a clinical RCT study that, house dust mite sublingual allergen immunotherapy (HDM-SLIT) increases viral-induced interferons and reduced alarmin IL-33 expression in HBECs. Our data suggest that allergic asthma patients who have a history of asthma exacerbations and recurrent respiratory infections could potentially benefit from AIT treatment.
In conclusion, our study has provided new understandings into how the interaction between allergens and viral infections influences the bronchial epithelial and smooth muscle cells to induce inflammation by producing alarmin cytokines as well as antiviral immunity in asthma.
Publishing year
2023-06-02
Language
English
Publication/Series
Lund University, Faculty of Medicine Doctoral Dissertation Series
Issue
2023:73
Full text
Document type
Dissertation
Publisher
Lund University, Faculty of Medicine
Topic
- Respiratory Medicine and Allergy
Keywords
- Asthma
- Aeroallergens
- Airway inflammation
- Bronchial epithelial cells
- Bronchial smooth muscle cells
- Metabolic DAMPs
- Proteases
- Allergen immunotherapy
- Mast cells
- Viral infections
- innate immunity
Status
Published
Research group
- Respiratory Immunopharmacology
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-8021-413-1
Defence date
2 June 2023
Defence time
13:00
Defence place
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Zoom: https://lu-se.zoom.us/j/62780109253?pwd=MW1wY2xPREdEU0wyS1prbjhwbmVuQT09
Opponent
- Madeleine Rådinger (professor)