Steady-state neutrophil homeostasis is a demand-driven process

Polymorphonuclear neutrophil granulocytes (neutrophils) represent a fundamental component of the innate immune system, forming an efficient barrier against invading microbial pathogens. Neutropenia, a common unwanted side effect of chemotherapy, is associated with infectious complications. The human bone marrow produces an estimated number of 10 neutrophils per day, and granulopoiesis physiologically takes up two-thirds of the hematopoietic marrow space. The regulation of neutrophil numbers in the steady state remains incompletely understood. More recent evidence, however, suggests that it depends on separate hematopoietic signaling pathways as compared with “emergency granulopoiesis,” elicited by injection of infectious agents into experimental mice. A “neutrostat” has been suggested to detect neutrophils released by the marrow (“turnstile” hypothesis) or, alternatively, to measure the number of apoptotic neutrophils phagocytosed by tissue macrophages. Indeed, adhesion molecule-deficient mice, whose neutrophils are unable to transmigrate, display pronounced neutrophilia. The underlying mechanism was elegantly shown to represent disinhibited macrophage-derived IL-23 secretion, which, in turn, stimulates TH 17 -derived IL-17 production. IL-17 boosts G-CSF secretion, which stimulates granulopoiesis. Further evidence derived from experiments in macrophage and dendritic cell-deficiency models confirm that phagocytes are able to generate a negative feedback signal for granulopoiesis (reviewed in ref. 2). However, marrow-derived Steady-state neutrophil homeostasis is a demand-driven process