Elimination of senescent neutrophils by TNF-related apoptosis-inducing [corrected] ligand.
Neutrophils are phagocytic effectors which are produced in the bone marrow and released into the circulation. Thereafter, they are either recruited to sites of inflammation or rapidly become senescent, return to the bone marrow, and undergo apoptosis. Stromal cell-derived factor 1 (SDF-1) coordinates the return of senescent neutrophils to the bone marrow by interacting with CXCR4 that is preferentially expressed on senescent neutrophils. We demonstrate that CXCR4 ligation by SDF-1 or other CXCR4 agonists significantly increases the expression of both TNF-related apoptosis-inducing [corrected] ligand (TRAIL) and of the death-inducing TRAIL receptors on neutrophils, which confers an acquired sensitivity to TRAIL-mediated death and results in TRAIL-dependent apoptosis. In vivo administration of TRAIL antagonists results in neutrophilic accumulation within the bone marrow and a reduction in neutrophil apoptosis; conversely recombinant TRAIL administration reduced neutrophil number within bone marrow. Thus, SDF-1 ligation of CXCR4 causes the parallel processes of chemotaxis and enhanced TRAIL and TRAIL death receptor expression, resulting in apoptosis of senescent neutrophils upon their return to the bone marrow.
Division of Infectious Diseases, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
Julian J
JJ
Lum
Gary
G
Bren
Rebecca
R
McClure
Andrew D
AD
Badley
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000276:immunology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D016350:Leucine Zippers; D007958:Leukocyte Count; D008024:Ligands; D008562:Membrane Glycoproteins / Q000819:agonists / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000819:agonists / Q000378:metabolism / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*
D019138:Antibodies, Blocking; D051017:Apoptosis Regulatory Proteins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D019718:Receptors, CXCR4; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha