CXCR2 and CXCR4 antagonistically  regulate neutrophil trafficking  from murine bone marrow.
Neutrophils are a major component of the innate immune response. Their homeostasis is maintained, in part, by the regulated release of neutrophils from the bone marrow. Constitutive expression of the chemokine CXCL12 by bone marrow stromal cells provides a key retention signal for neutrophils in the bone marrow through activation of its receptor, CXCR4. Attenuation of CXCR4 signaling leads to entry of neutrophils into the circulation through unknown mechanisms. We investigated the role of CXCR2-binding ELR+ chemokines in neutrophil trafficking using mouse mixed bone marrow chimeras reconstituted with Cxcr2(-/-) and WT cells. In this context, neutrophils lacking CXCR2 were preferentially retained in the bone marrow, a phenotype resembling the congenital disorder myelokathexis, which is characterized by chronic neutropenia. Additionally, transient disruption of CXCR4 failed to mobilize Cxcr2(-/-) neutrophils. However, neutrophils lacking both CXCR2 and CXCR4 displayed constitutive mobilization, showing that CXCR4 plays a dominant role in neutrophil trafficking. With regard to CXCR2 ligands, bone marrow endothelial cells and osteoblasts constitutively expressed the ELR+ chemokines CXCL1 and CXCL2, and CXCL2 expression was induced in endothelial cells during G-CSF-induced neutrophil mobilization. Collectively, these data suggest that CXCR2 signaling is a second chemokine axis that interacts antagonistically with CXCR4 to regulate neutrophil release from the bone marrow.
Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
Kyle J
KJ
Eash
Adam M
AM
Greenbaum
Priya K
PK
Gopalan
Daniel C
DC
Link
D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D054360:Chemokine CXCL1; D054377:Chemokine CXCL12; D054426:Chemokine CXCL2; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D010006:Osteoblasts / Q000276:immunology / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms
C499706:CXCL2 protein, human; D054360:Chemokine CXCL1; D054377:Chemokine CXCL12; D054426:Chemokine CXCL2; D018925:Chemokines; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor