Glucocorticoid-induced eosinopenia results from CXCR4-dependent bone marrow migration

Abstract

Glucocorticoids are considered first-line therapy in a variety of eosinophilic disorders. They lead to a transient, profound decrease in circulating human eosinophils within hours of administration. The phenomenon of glucocorticoid-induced eosinopenia has been the basis for the use of glucocorticoids in eosinophilic disorders, and it has intrigued clinicians for 7 decades, yet its mechanism remains unexplained. To investigate, we first studied the response of circulating eosinophils to in vivo glucocorticoid administration in 3 species and found that the response in rhesus macaques, but not in mice, closely resembled 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 positron emission tomography/computed tomography imaging, before and after administration of glucocorticoids. Glucocorticoids induced rapid bone marrow homing of eosinophils. The kinetics of glucocorticoid-induced eosinopenia and bone marrow migration were consistent with those of the induction of the glucocorticoid-responsive chemokine receptor CXCR4, and selective blockade of CXCR4 reduced or eliminated 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. The human study was registered at ClinicalTrials.gov as #NCT02798523.

Whole-Body Imaging to Assess Cell-Based Immunotherapy: Preclinical Studies with an Update on Clinical Translation

“…Labeled DCs can be activated and present antigen to T cells [17]. Chemotaxis is maintained in labeled bone marrow cells [64,65] and in eosinophils [32]. These studies suggest that the optimal labeling doses that provide sufficient PET detection while minimizing radiotoxicity are approximately 11-44 kBq/10 6 cells, depending on type and condition of the cells.…”

“…Zircconium-89 ( 89 Zr, 3.3-day half-life) has relatively low positron energy required for high-resolution imaging and lacks Auger electron emission [27]. 89 Zr-oxine has been recently developed as an agent to label cells ex vivo [17,28] and has successfully tracked various immune cell types for 1-2 weeks [17,[28][29][30][31][32] (Fig. 1a).…”

Imaging of cell-based therapy using 89Zr-oxine ex vivo cell labeling for positron emission tomography

“…Cell labeling with 89 Zr-oxine is straightforward and exerts minimal toxicity to labeled cells when optimal cell labeling doses were used. Although no clinical trials in humans have been performed, dosimetry data in non-human primates that received autologous NK cells showed very low radio-exposures to organs 64 , and no clinical side effects were observed with autologous transfer of NK cells, CD34 + HPSCs 64 and eosinophils 71 , confirming the safety of this method. Practically, labeling only a small fraction ( e.g.…”

“…To address this question, eosinophils purified from peripheral blood were labeled with 89 Zr-oxine, transferred back to the animal, and imaging was performed before and after glucocorticoid treatment. 89 Zr-oxine PET demonstrated a rapid increase of bone marrow accumulation of 89 Zr-oxine labeled eosinophils over a four-hour period after glucocorticoid treatment 71 . This demonstrates the high sensitivity of 89 Zr-oxine PET to detect rapid changes in cell distribution in response to exogenous stimuli.…”

Editorial: Smoldering Inflammation in Cardio-Immune-Metabolic Disorders

“…Pelaia et al extensively reviewed the central role of IL-5 in the pathogenesis of severe eosinophilic asthma. The latter condition can be responsive to inhaled and/or systemic glucocorticoids that reduce eosinophilia (Hong et al, 2020).…”