Background Although eosinophils co-express multiple integrin receptors, the contributions of integrins to eosinophil development have not been explored. We previously described extensive aggregation and cytological immaturity in eosinophils developing in bone-marrow (BM) cultures exposed to dexamethasone. Here we examined the relationship of α4 integrins with these effects of dexamethasone.
Objectives We evaluated: (a) the effects of exposure to dexamethasone in BM culture on eosinophil expression of α4 integrin receptors and ligands; (b) the contribution of α4 integrins to eosinophil aggregation and maturation.
Methods Cultures were established with IL-5 (alone or with dexamethasone) for up to 7 days, and eosinophil production, α4 integrin receptor/ligand expression, aggregation and morphology were evaluated before and after targeting α4 integrin-dependent adhesions. Because prostaglandin E2 (PGE2) modifies the effects of dexamethasone on eosinophilopoiesis, PGE2 effects on α4 integrin expression and function were also evaluated.
Results Dexamethasone increased the yield of eosinophils up to day 7. The frequency of eosinophils expressing α4, β1 and β7 integrin receptors at day 7 was also increased by dexamethasone. Eosinophils also expressed the α4β1 ligand, VCAM-1. Dexamethasone increased the expression of α4 integrin and VCAM-1 in aggregates containing eosinophils as early as day 3. PGE2, added up to day 3, modified the effects of dexamethasone to suppress the expression of α4 integrin, decrease aggregation and promote cytological maturation of eosinophils recovered at day 7. Dissociation of immature eosinophils from clusters present at day 3 by reagents targeting α4 or β1 integrins or VCAM-1 also induced cytological maturation. The concordant effects of targeting α4 integrins with drugs and antibodies support a relationship between α4-mediated aggregation and maturational arrest.
Conclusions These observations support a novel role for α4 integrin receptors and ligands in eosinophilopoiesis. In addition, increased α4 expression following glucocorticoid exposure may contribute to the retention and accumulation of eosinophils in haemopoietic tissue.