28 Feb Gene That Promotes Inflammation in Asthma Identified
MedicalResearch.com Interview with:
Zbigniew Zasłona PhD
Luke A. J. O’Neill PhD
Professor (Chair of Biochemistry)
School of Biochemistry and Immunology
Trinity Biomedical Sciences Institute
Trinity College Dublin, Dublin, Ireland
MedicalResearch.com: What is the background for this study?
Response: Asthma is the most common disease in childhood and the most common respiratory condition in Ireland. It is a disease of environmental and genetic components. It is important to point out that although Ireland has very good air quality, asthma prevalence is very high (the second highest in Europe), and although asthma is not a single gene disease (such as cystic fibrosis) it is very important to study genetic variations in Irish population.
Therefore in this study we put emphasis on the genetic component of asthma, rather than environmental factors, especially given that asthma heritability has been estimated as high as 60%. Prevention of asthma by reducing exposure to common risk factors, such as air pollution, will not stop the asthma epidemic in Ireland, as inferior air quality is not an issue.
MedicalResearch.com: What are the main findings?
Response: Caspase-11 is an innate immunity gene involved in bacterial recognition and LPS/danger signaling. Caspase-11 is a gene coding for a cysteine protease, which is a driver of pyroptosis – a highly inflammatory type of cell death. We have found a novel role for caspase-11. In our study we show that caspase-11 can provoke a damaging inflammatory reaction in the lungs irritated with allergen and is likely to be a key driver of allergic inflammation in the lungs of asthmatics.
MedicalResearch.com: What should readers take away from your report?
Response: Caspase-4 (homologue of murine caspase-11) expression is induced in human asthmatics. Our work provides convincing evidence to explore the idea of tackling inflammatory cell death in asthma and presents opportunity to explore inhibition of caspase-4 activity as a novel treatment for asthma. There is a strong genetic component of asthma and we believe that caspase-4 gene polymorphism, resulting in overreactive phenotype, may predispose certain patients to uncontrolled inflammatory cell death, which leads to disease.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Development of a specific Caspase-4 inhibitor would be of a great value. Testing it in asthma animal models and then in humans would be a next step. We feel it is worth to look for polymorphisms in regulatory sites of Caspase-4 among asthmatic patients. Moreover since caspase-4/11 has not yet been studied beyond bacterial infections, any new context of caspase-4/11 activity would be very informative from the scientific and therapeutic perspective.
Zbigniew Zasłona, Ewelina Flis, Mieszko M. Wilk, Richard G. Carroll, Eva M. Palsson-McDermott, Mark M. Hughes, Ciana Diskin, Kathy Banahan, Dylan G. Ryan, Alexander Hooftman, Alicja Misiak, Jay Kearney, Gunter Lochnit, Wilhelm Bertrams, Timm Greulich, Bernd Schmeck, Oliver J. McElvaney, Kingston H. G. Mills, Ed C. Lavelle, Małgorzata Wygrecka, Emma M. Creagh, Luke A. J. O’Neill. Caspase-11 promotes allergic airway inflammation. Nature Communications, 2020; 11 (1) DOI: 10.1038/s41467-020-14945-2
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