Neutrophil adhesion to E-selectin under shear promotes the redistribution and co-clustering of ADAM17 and its proteolytic substrate L-selectin

Ulrich Schaff, Polly E. Mattila, Scott I. Simon, Bruce Walcheck

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

E-selectin is expressed by the vascular endothelium and binds flowing neutrophils in the blood to facilitate their recruitment into the underlying tissue at sites of inflammation. L-selectin on neutrophils is engaged by E-selectin and undergoes rapid clustering and then coalescence in the trailing edge of polarizing cells. These processes are believed to increase the valency and capacity of L-selectin to signal CD18 integrin activity. Neutrophils, upon exiting the microvasculature, down-regulate their surface L-selectin through ectodomain shedding by a disintegrin and metalloprotease 17 (ADAM17). We reasoned that neutrophil tethering and rolling on E-selectin might initiate a coordinate change in the membrane distribution of ADAM17 as well. We found that ADAM17 indeed underwent a dramatic cell surface redistribution to the trailing edge of neutrophils rolling on purified E-selectin when activated by a chemoattractant under shear flow; however, its lateral migration occurred at a slower rate than L-selectin. ADAM17 and L-selectin also redistributed in the same manner in neutrophils attached to IL-1β-stimulated HUVEC under shear flow. In contrast, the coalescence of L-selectin on the surface of neutrophils by antibody cross-linking did not promote the redistribution of ADAM17, suggesting that these molecules do not constitutively associate in the plasma membrane. Together, our findings reveal that neutrophil activation upon E-selectin adhesion initiates active transport of ADAM17 and L-selectin to the cell uropod, thus providing additional insight into the molecular mechanisms that regulate L-selectin during leukocyte extravasation.

Original languageEnglish (US)
Pages (from-to)99-105
Number of pages7
JournalJournal of Leukocyte Biology
Volume83
Issue number1
DOIs
StatePublished - Jan 1 2008

Keywords

  • Ectodomain shedding
  • Inflammation

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