ICAM-1-activated Src and eNOS signaling increase endothelial cell surface PECAM-1 adhesivity and neutrophil transmigration

Guoquan Liu, Aaron T. Place, Zhenlong Chen, Viktor M. Brovkovych, Stephen M. Vogel, William A. Muller, Randal A. Skidgel, Asrar B. Malik, Richard D. Minshall*

*Corresponding author for this work

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Polymorphonuclear neutrophil (PMN) extravasation requires selectin-mediated tethering, intercellular adhesion molecule-1 (ICAM-1)-dependent firm adhesion, and platelet/endothelial cell adhesion molecule 1 (PECAM-1)-mediated transendothelial migration. An important unanswered question is whether ICAM-1 - activated signaling contributes to PMN transmigration mediated by PECAM-1. We tested this concept and the roles of endothelial nitric oxide synthase (eNOS) and Src activated by PMN ligation of ICAM-1 in mediating PECAM-1-dependent PMN transmigration. We observed that lung PMN infiltration in vivo induced in carrageenan-injectedWTmice was significantly reduced in ICAM-1-/- and eNOS-/- mice. Crosslinking WT mouse ICAM-1 expressed in human endothelial cells (ECs), but not the phospho-defective Tyr518Phe ICAM-1 mutant, induced SHP-2-dependent Src Tyr530 dephosphorylation that resulted in Src activation. ICAM-1 activation also stimulated phosphorylation of Akt (p-Ser473) and eNOS (p-Ser1177), thereby increasing NO production. PMN migration across EC monolayers was abolished in cells expressing the Tyr518Phe ICAM-1 mutant or by pretreatment with either the Src inhibitor PP2 or eNOS inhibitor L-NAME. Importantly, phospho-ICAM-1 induction of Src signaling induced PECAM-1 Tyr 686 phosphorylation and increased EC surface anti-PECAM-1 mAb-binding activity. These results collectively show that ICAM-1-activated Src and eNOS signaling sequentially induce PECAM-1 - mediated PMN transendothelial migration. Both Src and eNOS inhibition may be important therapeutic targets to prevent or limit vascular inflammation.

Original languageEnglish (US)
Pages (from-to)1942-1952
Number of pages11
JournalBlood
Volume120
Issue number9
DOIs
StatePublished - Aug 30 2012

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Liu, G., Place, A. T., Chen, Z., Brovkovych, V. M., Vogel, S. M., Muller, W. A., Skidgel, R. A., Malik, A. B., & Minshall, R. D. (2012). ICAM-1-activated Src and eNOS signaling increase endothelial cell surface PECAM-1 adhesivity and neutrophil transmigration. Blood, 120(9), 1942-1952. https://doi.org/10.1182/blood-2011-12-397430