Elizabeth A. Jacobsen, PhD

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.