Female sex hormones and the oral contraceptive pill modulate asthma severity through GLUT-1
Females are disproportionately affected by asthma. An increased understanding of how female sex hormones influence key pathophysiological processes that underpin asthma may identify new, more effective asthma therapies, particularly for females with severe, poorly controlled asthma. We assessed the effects of oral ethinylestradiol/levonorgestrel (representing OCP use) and depot-medroxyprogesterone acetate (DMPA) and estradiol injections on key features of experimental asthma, and determined their effects on glucose transporter-1 (GLUT-1). The effects of OCP use on clinical asthma outcomes, and the relationships between estrogen receptors and type 2 (T2), non-T2, and GLUT-1 responses, in clinical asthma were also determined. OCP and DMPA reduce T2 responses, disease features, and lung expression of GLUT-1, whereas estradiol increases lung expression of GLUT-1, and results in severe, corticosteroid-insensitive, neutrophil-enriched disease, in experimental asthma. OCP use is associated with reduced T2 cytokine and GLUT-1 responses in clinical asthma. GLUT-1 expression is increased in sputum of severe asthmatics, and positively correlates with estrogen receptor expression and both T2 and non-T2 inflammatory responses. Significantly, OCP or GLUT-1 inhibition protects against obesity-associated or estradiol-induced, severe, experimental asthma, respectively. Together, these data show how female sex hormones and the OCP likely modulate asthma severity by modifying GLUT-1 responses in the airways.
Authors
- Hayley A. Scott (ORCID: https://orcid.org/0000-0002-3201-8825)
- Emily Mills (ORCID: https://orcid.org/0000-0001-5527-5464)
- Jemma Mayall (ORCID: https://orcid.org/0000-0002-0915-5020)
- Richard Kim (ORCID: https://orcid.org/0000-0002-8709-5270)
- Alexandra C Brown
- Jay C. Horvat (ORCID: https://orcid.org/0000-0002-8526-0631)
- Katherine J. Baines (ORCID: https://orcid.org/0000-0002-4240-6581)
- Peter A. B. Wark (ORCID: https://orcid.org/0000-0001-5676-6126)
- Chantal Donovan (ORCID: https://orcid.org/0000-0003-4558-329X)
- James Pinkerton
- Lisa G. Wood (ORCID: https://orcid.org/0000-0002-0941-9225)
- Paul S. Foster
- Yike Guo (ORCID: https://orcid.org/0000-0002-3075-2161)
- Evan J. Williams (ORCID: https://orcid.org/0000-0003-0532-2060)
- Bronwyn S. Berthon (ORCID: https://orcid.org/0000-0001-7858-6513)
- Katie Wynne
- Nazanin Zounemat Kermani (ORCID: https://orcid.org/0000-0003-2479-3861)
- Ian Michael Adcock (ORCID: https://orcid.org/0000-0003-2101-8843)
- Philip M. Hansbro (ORCID: https://orcid.org/0000-0002-4741-3035)
- Olivia R. Carroll
- Sven-Erik Dahlen
- Henry M. Gomez (ORCID: https://orcid.org/0000-0001-9255-5705)
- Samantha L E Vinzenz
Institutions
- University of Technology Sydney (AU)
- Karolinska University Hospital (SE)
- Hong Kong University of Science and Technology (HK)
- Centenary Institute (AU)
- Woolcock Institute of Medical Research (AU)
- Karolinska Institutet (SE)
- Hunter Medical Research Institute (AU)
- Lung Institute (US)
- NIHR Imperial Biomedical Research Centre (GB)
- Imperial College London (GB)
- University of Newcastle Australia (AU)
Publication Details
- Journal
- Mucosal Immunology
- Published
- 2025-02-26
- DOI
- https://doi.org/10.1016/j.mucimm.2025.02.006
- Citations
- 4
- Primary Topic
- Asthma and respiratory diseases
- Type
- article
- Field-Weighted Citation Impact
- 4.66
Funders
- European Federation of Pharmaceutical Industries and Associations
- European Commission
- Hunter Medical Research Institute