Key Points
Gα13 plays a role in integrin-dependent neutrophil transendothelial migration.
Gα13 enhances motility but did not affect directionality of neutrophil migration.
Integrin outside-in signaling mediates Gα13-dependent neutrophil migration.
Abstract
Neutrophil migration requires β2 integrins and chemoattractant receptor signaling for motility and directionality. G protein subunit Gα13 can facilitate cell migration by mediating RhoA activation induced by G protein–coupled receptors. However, the possible role of Gα13-integrin interaction in migration is unclear. In this study, we show that Gα13−/− neutrophils are deficient in transendothelial migration and migration on β2 integrin ligand ICAM-1. However, unlike G protein–coupled receptors and integrin inside-out signaling pathways, Gα13 is important in migration velocity and neutrophil spreading but not in directionality nor cell adhesion. Importantly, neutrophil recruitment in vivo was also inhibited in Gα13−/− mice, suggesting the importance of Gα13 in transendothelial migration of neutrophils in vitro and in vivo. Furthermore, a synthetic peptide (MB2mP6) derived from the Gα13 binding site of β2 inhibited Gα13-β2 interaction and Gα13-mediated transient RhoA inhibition in neutrophils, suggesting that this peptide inhibited integrin outside-in signaling. MB2mP6 inhibited migration of control neutrophils through endothelial cell monolayers or ICAM-1–coated filters, but was without further effect on Gα13−/− neutrophils. It also inhibited integrin-dependent neutrophil migration velocity without affecting directionality. In vivo, MB2mP6 markedly inhibited neutrophil infiltration into the cardiac tissues induced by ischemia/reperfusion injury. Thus, Gα13-dependent outside-in signaling enables integrin-dependent neutrophil motility without affecting directionality and may be a new therapeutic target for inhibiting neutrophil trafficking but not adhesion.
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Footnotes
This work was supported by National Heart, Lung and Blood Institute Grants R35HL150797 (X.D.), RO1HL125356 (X.D.), RO1HL080264 (X.D.), R43 HL142396 (R.A.S.), and R44 HL142396 (R.A.S.).
The online version of this article contains supplemental material.
Abbreviations used in this article
- fMIVIL
- N-formyl-Met-Ile-Val-Ile-Leu
- GEF
- guanine nucleotide exchange factor
- GPCR
- G protein-coupled receptor
- HLPN
- high-loading peptide nanoparticle
- MI/R
- myocardial ischemia/reperfusion
- Received January 8, 2021.
- Accepted October 7, 2021.
- Copyright © 2021 by The American Association of Immunologists, Inc.
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