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 accumulation of neutrophils in the circulation or altered hematopoiesis mediated by a disrupted regulatory feedback loop. Chimeric mice were generated by transplanting various ratios of CD18(+/+) and CD18(-/-) unfractionated bone marrow cells into lethally irradiated wild-type mice, resulting in approximately 0%, 10%, 50%, 90%, or 100% CD18 null neutrophils in the blood. The presence of only 10% CD18(+/+) neutrophils was sufficient to prevent the severe neutrophilia seen in mice reconstituted with CD18(-/-) bone marrow cells. These data show that the neutrophilia in CD18(-/-) mice is not caused by enhanced neutrophil survival or the inability of neutrophils to leave the vascular compartment. In CD18(-/-), CD18(-/-)E(-/-), CD18(-/-)P(-/-), EP(-/-), and EPI(-/-) mice, levels of granulocyte colony-stimulating factor (G-CSF) and interleukin-17 (IL-17) were elevated in proportion to the neutrophilia seen in these mice, regardless of the underlying mutation. Antibiotic treatment or the propensity to develop skin lesions did not correlate with neutrophil counts. Blocking IL-17 or G-CSF function in vivo significantly reduced 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.
Forlow
S B
SB
Department of Biomedical Engineering and Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Schurr
J R
JR
Kolls
J K
JK
Bagby
G J
GJ
Schwarzenberger
P O
PO
Ley
K
K
D000818:Animals; D016026:Bone Marrow Transplantation; D018821:CD18 Antigens / Q000032:analysis / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000172:deficiency*; D019040:E-Selectin / Q000032:analysis / Q000502:physiology; D005246:Feedback; D016179:Granulocyte Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology* / Q000502:physiology; D006098:Granulocytes / Q000502:physiology*; D006410:Hematopoiesis; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000502:physiology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology* / Q000502:physiology; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000737:chemistry / Q000166:cytology; D019007:P-Selectin / Q000032:analysis / Q000502:physiology; D018183:Transplantation Chimera
D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D020381:Interleukin-17; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor