Elizabeth A. Jacobsen, PhD
Mayo Clinic Arizona
Why are Eosinophils Resistant to Steroid Treatment for Severe Asthma?
- Innovation Award
- basic biologic mechanisms
Using isolated and pure populations of blood-derived eosinophils, we identified that IL-33 pre-treatment of eosinophils results in a long-lasting and maintained resistance to steroid-induced cell death. Strikingly, removal of IL-33 prior to steroid treatment maintains protection from steroid-induced cell death. This suggests that targeting of downstream pathways of IL-33 may add beneficial results for blocking steroid-resistance of eosinophils. We are in the process of investigating these intracellular pathways. To test the role of IL-33 in the lung environment, we used translational models of asthma that are IL-33-dependent or independent and found IL-33 is critical for suppressing steroid-induced eosinophil cell death in vivo. When compared to mice that have an eosinophil-specific deletion of the glucocorticoid receptor for steroids (i.e., steroid resistant eosinophils), the degree of eosinophilia and ILC2 in the lungs were comparable, indicating IL-33 administration results in airway inflammation similar to that of a model of eosinophil steroid-resistant asthma. These findings provide novel insights into mechanisms of IL-33 in mediating eosinophil resistance to steroid-induced cell death in asthma and will help lay the foundation for future studies for interventional strategies for treatment.
Update: Some people with severe eosinophilic asthma are refractory to high doses of steroid treatment, resulting in greater morbidity and financial burden. We identified that a cytokine often found elevated in people with severe asthma, IL-33, is critical to the survival and activation of eosinophils, a causative agent of pathology in asthma. We have conducted in vitro and translational asthma model studies demonstrating that IL-33 promotes prolonged survival of eosinophils even upon steroid treatment. These findings lay the foundation for further investigation into the pathways that mediate this resistance for future targets for intervention.
Page last updated: October 6, 2022
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