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CD177 modulates human neutrophil migration through activation-mediated integrin and chemoreceptor regulation

Ming Bai, Ricardo Grieshaber-Bouyer, Junxia Wang, Angela B. Schmider, Zachary S. Wilson, Liling Zeng, Olha Halyabar, Matthew D. Godin, Hung N. Nguyen, Anaïs Levescot, Pierre Cunin, Craig T. Lefort, Roy J. Soberman and Peter A. Nigrovic

Key Points

  • Ligation of CD177, a GPI-linked surface protein expressed selectively on neutrophils, blocks neutrophil migration independently of PECAM-1.

  • Blockade reflects activation through β2 integrins, immobilizing cells via stronger integrin attachments and impaired chemokine signaling.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

CD177 is a glycosylphosphatidylinositol (GPI)-anchored protein expressed by a variable proportion of human neutrophils that mediates surface expression of the antineutrophil cytoplasmic antibody antigen proteinase 3. CD177 associates with β2 integrins and recognizes platelet endothelial cell adhesion molecule 1 (PECAM-1), suggesting a role in neutrophil migration. However, CD177pos neutrophils exhibit no clear migratory advantage in vivo, despite interruption of in vitro transendothelial migration by CD177 ligation. We sought to understand this paradox. Using a PECAM-1-independent transwell system, we found that CD177pos and CD177neg neutrophils migrated comparably. CD177 ligation selectively impaired migration of CD177pos neutrophils, an effect mediated through immobilization and cellular spreading on the transwell membrane. Correspondingly, CD177 ligation enhanced its interaction with β2 integrins, as revealed by fluorescence lifetime imaging microscopy, leading to integrin-mediated phosphorylation of Src and extracellular signal-regulated kinase (ERK). CD177-driven cell activation enhanced surface β2 integrin expression and affinity, impaired internalization of integrin attachments, and resulted in ERK-mediated attenuation of chemokine signaling. We conclude that CD177 signals in a β2 integrin-dependent manner to orchestrate a set of activation-mediated mechanisms that impair human neutrophil migration.

  • Submitted March 2, 2017.
  • Accepted August 10, 2017.
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