Illustration outlining the relationship between neutrophil maturation, bone marrow release, and cellular responsiveness of CXCR4 receptor to the ligand CXCL12. As neutrophils mature in healthy individuals, the cell-surface expression of CXCR4 and responsiveness to CXCL12 are reduced (darker cells). Once in the periphery, cell-surface expression and responsiveness to CXCL12 increase as these neutrophils age (lighter cells), allowing relocalization to CXCL12 secreting niches. In cells expressing CXCR4 truncation mutants, down-regulation after receptor activation is impaired. As a result, the mutant receptor remains continuously responsive to CXCL12 produced by bone marrow stromal cells. Blockade of the CXCR4 receptor with plerixafor permits mutant neutrophils to escape the constant signaling loop that otherwise keeps mature neutrophils trapped in the bone marrow. This schema is presented as a probable mechanism for correction of the neutrophil trafficking defect. McDermott et al speculate that release from the bone marrow may also be the mechanism by which plerixafor corrects the lymphopenia of WHIM syndrome.¹