Regulation of granulopoiesis: lessons from leukocyte adhesion deficiency

The mechanisms that regulate granulopoiesis, in particular, stress (or “emergency”) granulopoiesis, are incompletely understood. Studies of granulocyte colony-stimulating factor (G-CSF) or G-CSF receptor–deficient mice provide strong evidence that G-CSF is the principal hematopoietic cytokine regulating basal granulopoiesis. But there is evidence that stress granulopoiesis may be regulated in both a G-CSF–dependent and –independent fashion. For example, in G-CSF–deficient mice, the neutrophil response to infection with Listeria monocytogenes is impaired (Lieschke et al, Blood. 1994;84:1737-1746), whereas it is normal after challenge with Candida albicans (Basu et al, Blood. 2000;95:3725-3733). In any event, the signals that regulate the release of G-CSF or other granulopoietic cytokines are poorly characterized.

Forlow and colleagues (page 3309) examine the mechanisms responsible for the neutrophilia associated with CD18 (β2-integrin) deficiency. Based on their data and data generated by Horwitz and colleagues using a similar strategy (Blood. 2001;97:1578-1583), the authors suggest the novel hypothesis that granulopoiesis may be regulated through a feedback loop sensing neutrophil accumulation in peripheral tissues. Moreover, evidence is provided suggesting that IL-17, through stimulation of G-CSF release, is driving granulopoiesis in CD18-deficient mice. These provocative findings raise several important questions. Because CD18 deficiency results in a marked susceptibility to infection, what role, if any, do subclinical infections play in driving granulopoiesis in these mice? What cell type or types are responsible for the production of IL-17 in this pathway, and how do they sense the number of neutrophils present in tissues? Clearly, there are IL-17– and G-CSF–independent pathways regulating granulopoiesis; what are the components  of these pathways, and how are they regulated? The present study suggests an exciting new avenue of granulopoiesis research, one that eventually may lead to novel strategies to modulate neutrophil production.