Live cell tracking in a rhesus macaque model reveals that glucocorticoids induce bone marrow migration of eosinophils.
The effect is dependent on the glucocorticoid-responsive chemokine receptor CXCR4.
Glucocorticoids are considered first-line therapy in a variety of eosinophilic disorders. They lead to a transient, profound drop in circulating human eosinophils within hours of administration. This phenomenon of glucocorticoid-induced eosinopenia was the basis for the use of glucocorticoids in eosinophilic disorders and it has intrigued clinicians for seven decades, yet it remains unexplained. To address this, we first studied the response of circulating eosinophils to in vivo glucocorticoid administration in three species and found that the response in rhesus macaques, but not in mice, closely resembles that in humans. We then developed an isolation technique to purify rhesus macaque eosinophils from peripheral blood and performed live tracking of zirconium-89-oxine labeled eosinophils by serial PET/CT imaging before and after glucocorticoid administration. We found that glucocorticoids induce rapid bone marrow homing of eosinophils. The kinetics of glucocorticoid-induced eosinopenia and of bone marrow migration are consistent with those of the induction of the glucocorticoid-responsive chemokine receptor CXCR4, and selective blockade of CXCR4 reduces or eliminates the early glucocorticoid-induced reduction in blood eosinophils. Our results indicate that glucocorticoid-induced eosinopenia results from CXCR4-dependent migration of eosinophils to the bone marrow. These findings provide insight into the mechanism of action of glucocorticoids in eosinophilic disorders, with implications for the study of glucocorticoid resistance and the development of more targeted therapies.