Interaction between integrin alpha9beta1 and vascular cell adhesion molecule-1 (VCAM-1) inhibits neutrophil apoptosis.
According to the prevailing paradigm, neutrophils are short-lived cells that undergo spontaneous apoptosis within 24 hours of their release from the bone marrow. However, neutrophil survival can be significantly prolonged within inflamed tissue by cytokines, inflammatory mediators, and hypoxia. During screening experiments aimed at identifying the effect of the adhesive microenvironment on neutrophil survival, we found that VCAM-1 (CD106) was able to delay both spontaneous and Fas-induced apoptosis. VCAM-1-mediated survival was as efficient as that induced by the cytokine IFN-beta and provided an additive, increased delay in apoptosis when given in combination with IFN-beta. VCAM-1 delivered its antiapoptotic effect through binding the integrin alpha9beta1. The alpha9beta1 signaling pathway shares significant features with the IFN-beta survival signaling pathway, requiring PI3 kinase, NF-kappaB activation, as well as de novo protein synthesis, but the kinetics of NF-kappaB activation by VCAM-1 were slower and more sustained compared with IFN-beta. This study demonstrates a novel functional role for alpha9beta1 in neutrophil biology and suggests that adhesive signaling pathways provide an important extrinsic checkpoint for the resolution of inflammatory responses in tissues.
Ross
Ewan A
EA
Division of Immunity and Infection, Medical Research Council (MRC) Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, United Kingdom.
Douglas
Mike R
MR
Wong
See Heng
SH
Ross
Emma J
EJ
Curnow
S John
SJ
Nash
Gerard B
GB
Rainger
Ed
E
Scheel-Toellner
Dagmar
D
Lord
Janet M
JM
Salmon
Mike
M
Buckley
Christopher D
CD
D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D007249:Inflammation / Q000276:immunology; D016023:Integrins / Q000276:immunology*; D016899:Interferon-beta / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology
D016023:Integrins; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D019014:fas Receptor; C113256:integrin alpha 9 beta 1; D016899:Interferon-beta; D019869:Phosphatidylinositol 3-Kinases