Leukocytes are known to exacerbate inflammatory and vaso-occlusive processes in sickle cell disease (SCD). The aim of this study was to determine whether alterations in neutrophil maturity and/or cell-death modulating factors in the circulation contribute to the increased leukocyte counts and leukocyte survival observed in SCD. The maturity of circulating neutrophils from healthy control individuals (CON), SCD and SCD patients on hydroxyurea therapy (SCDHU) was determined immunophenotypically. Serum factors affecting neutrophil apoptosis (determined by annexin V-binding) were analyzed by culturing control neutrophils (CON neutrophils) with pooled serum from CON, SCD and SCDHU individuals. Immunophenotypic characterization of neutrophils suggested a slight, but significant, increase in the circulation of immature neutrophils in SCD. While SCD neutrophils cultured in the presence of CON serum presented delayed apoptosis, unexpectedly, the culture of CON neutrophils with SCD serum significantly augmented apoptosis and caspase-9 activity. Inhibition of the activity of serum interleukin-8, a neutrophil-apoptosis-inhibiting cytokine, significantly increased SCD serum-induced CON neutrophil apoptosis, indicating that SCD serum may have both apoptotic and antiapoptotic properties. The decreased maturity of SCD neutrophils observed is suggestive of an accelerated immigration of leukocytes from the bone marrow to the circulating pool that may contribute to an increase in cell survival, subject to modulation by a complex balance of both anti- and proapoptotic factors contained in the circulation of SCD individuals.2361239-46