Aspergillus fumigatus -Secreted Alkaline Protease 1 Mediates Airways Hyperresponsiveness in Severe Asthma

The hallmark features of allergic asthma are type 2 (eosinophilic) inflammation and airways hyperresponsiveness (AHR). Although these features often comanifest in mouse lungs in vivo, we demonstrate in this study that the serine protease Alp1 from the ubiquitous mold and allergen, , can induce AHR i...

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Bibliographic Details
Published in:ImmunoHorizons 2019-08, Vol.3 (8), p.368-377
Main Authors: Redes, Jamie L, Basu, Trisha, Ram-Mohan, Sumati, Ghosh, Chandra C, Chan, Eunice C, Sek, Albert C, Zhao, Ming, Krishnan, Ramaswamy, Rosenberg, Helene F, Druey, Kirk M
Format: Article
Language:English
Subjects:
Allergens - immunology
Animals
Aspergillus fumigatus - enzymology
Aspergillus fumigatus - immunology
Asthma - immunology
Asthma - microbiology
Bronchoalveolar Lavage Fluid - cytology
Bronchoalveolar Lavage Fluid - immunology
Bronchoconstriction - drug effects
Bronchoconstriction - immunology
Cells, Cultured
Disease Models, Animal
Fungal Proteins - immunology
Gene Knockout Techniques
Humans
Inflammation - immunology
Lung - pathology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Myocytes, Smooth Muscle - immunology
Receptor, PAR-2 - genetics
Receptor, PAR-2 - immunology
Serine Endopeptidases - immunology
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Summary:The hallmark features of allergic asthma are type 2 (eosinophilic) inflammation and airways hyperresponsiveness (AHR). Although these features often comanifest in mouse lungs in vivo, we demonstrate in this study that the serine protease Alp1 from the ubiquitous mold and allergen, , can induce AHR in mice unable to generate eosinophilic inflammation. Strikingly, Alp1 induced AHR in mice devoid of protease-activated receptor 2/F2 trypsin-like receptor 1 (PAR2/F2RL1), a receptor expressed in lung epithelium that is critical for allergic responses to protease-containing allergens. Instead, using precision-cut lung slices and human airway smooth muscle cells, we demonstrate that Alp1 directly increased contractile force. Taken together, these findings suggest that Alp1 induces bronchoconstriction through mechanisms that are largely independent of allergic inflammation and point to a new target for direct intervention of fungal-associated asthma.
ISSN:2573-7732
2573-7732
DOI:10.4049/immunohorizons.1900046