Increased granulopoiesis through interleukin-17 and granulocyte colony-stimulating factor in leukocyte adhesion molecule-deficient mice

Many mutant mice deficient in leukocyte adhesion molecules display altered hematopoiesis and neutrophilia. This study investigated whether peripheral blood neutrophil concentrations in these mice are elevated as a result of a ccumulation of neutrophils in the circulation or altered hematopoiesis medi ated by a disrupted regulatory feedback loop. Chimeric mice were generated by transplanting various ratios of CD18(+/+) and CD18(-/-) unfractionated b one marrow cells into lethally irradiated wild-type mice, resulting in appr oximately 0%, 10%, 50%, 90%, or 100% CD18 null neutrophils in the blood. Th e presence of only 10% CD18(+/+) neutrophils Was sufficient to prevent the severe neutrophilia seen in mice reconstituted with CD18(-/-) bone marrow c ells. These data show that the, neutroohilia in CD18(-/-) mice is not cause d by enhanced neutrophil survival or the inability of neutrophils to leave the vascular compartment. In CD18(-/-), CD18(-/-)E(-/-), CD18(-/-)P(-/-), E P-/-, and EPI-/- mice, levels of granulocyte colony-stimulating factor (G-C SF) and interleukin-17 (IL-17) were elevated in proportion to the neutrophi lia seen in these mice, regardless of the underlying mutation. Antibiotic t reatment or the propensity to develop skin lesions did not correlate with n eutrophil, counts. Blocking IL-17 or G-CSF function in vivo significantly r educed neutrophil counts in severely neutrophilic mice by approximately 50% (P < .05) or 70% (P < .01), respectively. These data show that peripheral blood. neutrophil numbers are regulated by a feedback loop involving G-CSF and IL-17 and that this feedback loop is disrupted When neutrophils cannot migrate into peripheral tissues. (Blood. 2001;98: 3309-3314) (C) 2001 by Th e American Society of Hematology.