Vitronectin inhibits efferocytosis through interactions with apoptotic cells as well as with macrophages.
Effective removal of apoptotic cells, particularly apoptotic neutrophils, is essential for the successful resolution of acute inflammatory conditions. In these experiments, we found that whereas interaction between vitronectin and integrins diminished the ability of macrophages to ingest apoptotic cells, interaction between vitronectin with urokinase-type plasminogen activator receptor (uPAR) on the surface of apoptotic cells also had equally important inhibitory effects on efferocytosis. Preincubation of vitronectin with plasminogen activator inhibitor-1 eliminated its ability to inhibit phagocytosis of apoptotic cells. Similarly, incubation of apoptotic cells with soluble uPAR or Abs to uPAR significantly diminished efferocytosis. In the setting of LPS-induced ALI, enhanced efferocytosis and decreased numbers of neutrophils were found in bronchoalveolar lavage obtained from vitronectin-deficient (vtn(-/-)) mice compared with wild type (vtn(+/+)) mice. Furthermore, there was increased clearance of apoptotic vtn(-/-) as compared with vtn(+/+) neutrophils after introduction into the lungs of vtn(-/-) mice. Incubation of apoptotic vtn(-/-) neutrophils with purified vitronectin before intratracheal instillation decreased efferocytosis in vivo. These findings demonstrate that the inhibitory effects of vitronectin on efferocytosis involve interactions with both the engulfing phagocyte and the apoptotic target cell.
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA.
Hong-Beom
HB
Bae
Jean-Marc
JM
Tadie
Shaoning
S
Jiang
Dae Won
DW
Park
Celeste P
CP
Bell
Lawrence C
LC
Thompson
Cynthia B
CB
Peterson
Victor J
VJ
Thannickal
Edward
E
Abraham
Jaroslaw W
JW
Zmijewski
D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D002452:Cell Count; D018920:Coculture Techniques; D005260:Female; D008070:Lipopolysaccharides; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects* / Q000276:immunology; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology; D055293:Receptors, Urokinase Plasminogen Activator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D060168:Thymocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D019096:Vitronectin / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
D000906:Antibodies; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; C524899:Plaur protein, mouse; D055293:Receptors, Urokinase Plasminogen Activator; D019096:Vitronectin