IL-33 precedes IL-5 in regulating eosinophil commitment and is required for eosinophil homeostasis

Abstract

Eosinophils are important in the pathogenesis of many diseases, including asthma, eosinophilic esophagitis, and eczema. While IL-5 is crucial for supporting mature eosinophils, the signals that support earlier eosinophil lineage events are less defined. The IL-33 receptor, ST2, is expressed on several inflammatory cells, including eosinophils, and is best characterized for its role during the initiation of allergic responses in peripheral tissues. Recently, ST2 expression was described on hematopoietic progenitor subsets, where its function remains controversial. Our findings demonstrate that IL-33 is required for basal eosinophil homeostasis, since both IL-33– and ST2-deficient mice exhibited diminished peripheral blood eosinophil numbers at baseline. Exogenous IL-33 administration increased mature eosinophils in both the bone marrow and periphery in WT and IL-33–deficient, but not ST2-deficient, mice. Systemic IL-5 was also increased under this treatment, and blocking IL-5 with a neutralizing antibody ablated of the IL-33-induced mature eosinophil expansion. The homeostatic hypereosinophilia seen in IL-5–transgenic mice was significantly lower with ST2 deficiency despite similar elevations in systemic IL-5. Finally, in vitro treatment of bone marrow cells with IL-33, but not IL-5, led to specific early expansion of IL-5Rα–expressing precursor cells. In summary, our findings establish a basal defect in eosinophilopoiesis in IL-33– and ST2-deficient mice and a mechanism whereby IL-33 supports mature eosinophils by driving both systemic IL-5 production and the expansion of IL-5Rα–expressing precursor cells.