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

Author:

Molteni Raffaella12,Crespo Carolina Lage12,Feigelson Sara3,Moser Christian4,Fabbri Monica12,Grabovsky Valentin3,Krombach Fritz4,Laudanna Carlo5,Alon Ronen3,Pardi Ruggero12

Affiliation:

1. San Raffaele University School of Medicine and

2. Scientific Institute San Raffaele, Milano, Italy;

3. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel;

4. Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany; and

5. Division of General Pathology, Department of Pathology, School of Medicine, and the Center for Biomedical Computing (CBMC), University of Verona, Verona, Italy

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 β1 and β2 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 co-operatively control subsecond adhesion as well as postarrest adhesion stabilization. Thus, receptor-induced Gαi and β-arrestins act sequentially and in spatially distinct compartments to promote optimal KC-induced integrin-dependent adhesion during leukocyte extravasation.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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