CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions.
The number of neutrophils in the blood is tightly regulated to ensure adequate protection against microbial pathogens while minimizing damage to host tissue. Neutrophil homeostasis in the blood is achieved through a balance of neutrophil production, release from the bone marrow, and clearance from the circulation. Accumulating evidence suggests that signaling by CXCL12, through its major receptor CXCR4, plays a key role in maintaining neutrophil homeostasis. Herein, we generated mice with a myeloid lineage-restricted deletion of CXCR4 to define the mechanisms by which CXCR4 signals regulate this process. We show that CXCR4 negatively regulates neutrophil release from the bone marrow in a cell-autonomous fashion. However, CXCR4 is dispensable for neutrophil clearance from the circulation. Neutrophil mobilization responses to granulocyte colony-stimulating factor (G-CSF), CXCL2, or Listeria monocytogenes infection are absent or impaired, suggesting that disruption of CXCR4 signaling may be a common step mediating neutrophil release. Collectively, these data suggest that CXCR4 signaling maintains neutrophil homeostasis in the blood under both basal and stress granulopoiesis conditions primarily by regulating neutrophil release from the bone marrow.
Eash
Kyle J
KJ
Department of Medicine, Divisions of Oncology, Washington University School of Medicine, St Louis, MO, USA.
Means
Jacquelyn M
JM
White
Douglas W
DW
Link
Daniel C
DC
D019264:Adoptive Transfer; D000818:Animals; D001853:Bone Marrow / Q000502:physiology*; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D005260:Female; D005434:Flow Cytometry; D006098:Granulocytes / Q000166:cytology / Q000382:microbiology* / Q000502:physiology*; D008089:Listeria monocytogenes / Q000254:growth & development*; D008099:Liver / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D010537:Peritoneum / Q000378:metabolism / Q000382:microbiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism / Q000382:microbiology
C514936:CXCR4 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4