Rapid and recurrent neutrophil mobilization regulated by T134, a CXCR4 peptide antagonist.
The CXCR4/stromal cell-derived factor-1 (SDF-1) axis plays important roles in development, leukocyte trafficking, HIV infection, and tumorigenesis. Its critical function in bone marrow stem cell and hematopoietic progenitor cell retention, homing and release has been well-characterized by genetic and pharmacological analyses. However, its role in neutrophil retention and release is still poorly understood. In this study, we demonstrated that T134, a peptide antagonist of human CXCR4, is also a potent antagonist of mouse CXCR4. Treatment of C57BL/6 mice with T134 resulted in a rapid and time-dependent increase of white blood cells (WBC) and neutrophils, as well as hematopoietic stem and progenitor cells in peripheral blood. Interestingly, recurrent WBC and neutrophil mobilization was achieved by repeated T134 treatment, and the T134-mediated increase and subsequent retreat of WBC and neutrophils correlated with T134 activity in the peripheral blood. Kinetic analysis revealed that T134 binding to CXCR4 did not induce any significant cell-surface receptor downregulation, indicating that T134-induced WBC and neutrophil mobilization is likely due to direct blockage of the CXCR4/SDF-1 interaction. The results from this study support an important role of CXCR4/SDF-1 axis in neutrophil retention and release in the marrow.
Iyer
Chandrasekar V
CV
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Evans
Robert J
RJ
Lou
Qinyuan
Q
Lin
Datian
D
Wang
Jian
J
Kohn
Wayne
W
Yan
Liang Zeng
LZ
Pulley
Shon
S
Peng
Sheng-Bin
SB
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006397:Hematinics / Q000097:blood / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects*; D009842:Oligopeptides / Q000097:blood / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D013047:Specific Pathogen-Free Organisms
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D006397:Hematinics; D009842:Oligopeptides; D019718:Receptors, CXCR4; C116978:T134 peptide