β-Arrestin 2 is required for the induction and strengthening of integrin-mediated leukocyte adhesion during CXCR2-driven extravasation

Raffaella Molteni, Carolina Lage Crespo, Sara Feigelson, Christian Moser, Monica Fabbri, Valentin Grabovsky, Fritz Krombach, Carlo Laudanna, Ronen Alon, Ruggero Pardi

Research output: Contribution to journalArticle

Abstract

Leukocyte extravasation involves interdependent signaling pathways underlying the complex dynamics of firm adhesion, crawling, and diapedesis. While signal transduction by agonist-bound chemokine receptors plays a central role in the above responses, it is unclear how it contributes to the sustained and concurrent nature of such responses, given the rapid kinetics of chemokine-induced trimeric G protein coupling and homologous desensitization. Our findings unveil a novel role of β-arrestins in regulating the activation of signaling pathways underlying discrete integrin-mediated steps in CXCR2-driven leukocyte extravasation. By combining in vivo approaches in β-arrestin knockout mice with in vitro studies in engineered cellular models, we show that membrane-recruited β-arrestin 2 is required for the onset and maintenance of shear stress-resistant leukocyte adhesion mediated by both β 1 and β 2 integrins. While both β-arrestin isoforms are required for rapid keratinocyte-derived chemokine (KC)-induced arrest onto limiting amounts of vascular cell adhesion molecule-1 (VCAM-1), adhesion strengthening under shear is selectively dependent on β-arrestin 2. The latter synergizes with phospholipase C in promoting activation of Rap1A and B, both of which cooperatively control subsecond adhesion as well as postarrest adhesion stabilization. Thus, receptor-induced Gα i and β-arrestins act sequentially and in spatially distinct compartments to promote optimal KC-induced integrin-dependent adhesion during leukocyte extravasation.

Original languageEnglish
Pages (from-to)1073-1082
Number of pages10
JournalBlood
Volume114
Issue number5
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Immunology
  • Hematology

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