Beta-arrestin 2 is required for the induction and strengthening of integrin-mediated leukocyte adhesion during CXCR2-driven extravasation.
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 beta-arrestins in regulating the activation of signaling pathways underlying discrete integrin-mediated steps in CXCR2-driven leukocyte extravasation. By combining in vivo approaches in beta-arrestin knockout mice with in vitro studies in engineered cellular models, we show that membrane-recruited beta-arrestin 2 is required for the onset and maintenance of shear stress-resistant leukocyte adhesion mediated by both beta(1) and beta(2) integrins. While both beta-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 beta-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 Galpha(i) and beta-arrestins act sequentially and in spatially distinct compartments to promote optimal KC-induced integrin-dependent adhesion during leukocyte extravasation.
San Raffaele University School of Medicine, 20132 Milano, Italy.
Raffaella
R
Molteni
Carolina Lage
CL
Crespo
Sara
S
Feigelson
Christian
C
Moser
Monica
M
Fabbri
Valentin
V
Grabovsky
Fritz
F
Krombach
Carlo
C
Laudanna
Ronen
R
Alon
Ruggero
R
Pardi
D000818:Animals; D019390:Arrestins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D039041:Integrin alpha4beta1 / Q000502:physiology; D015603:Keratinocytes / Q000502:physiology; D015471:Leukemia, Basophilic, Acute / Q000473:pathology; D036904:Leukocyte Rolling / Q000502:physiology*; D007962:Leukocytes / Q000166:cytology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D033081:Shear Strength; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014699:Venules; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605258:Arrb2 protein, mouse; C000605257:Arrb2 protein, rat; D019390:Arrestins; D018076:DNA, Complementary; D039041:Integrin alpha4beta1; D034741:RNA, Small Interfering; D023063:Receptors, Interleukin-8B; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins