Abstract

Immune cells congregate at specific loci to fight infections during inflammatory responses, a process that must be transient and self-resolving. Cell dispersal promotes resolution, but it remains unclear how transition from clustering to dispersal is regulated. Here we show, using quantitative live imaging in zebrafish, that differential ligand-induced trafficking of chemokine receptors such as Cxcr1 and Cxcr2 orchestrates the state of neutrophil congregation at sites of tissue damage. Through receptor mutagenesis and biosensors, we show that Cxcr1 promotes clustering at wound sites, but is promptly desensitized and internalized, which prevents excess congregation. By contrast, Cxcr2 promotes bidirectional motility and is sustained at the plasma membrane. Persistent plasma membrane residence of Cxcr2 prolongs downstream signaling and is required for sustained exploratory motion conducive to dispersal. Thus, differential trafficking of two chemokine receptors allows coordination of antagonistic cell behaviors, promoting a self-resolving migratory response.

Highlights

  • This occurs at the expense of global space exploration and the encounter of alternative signals nearby

  • We demonstrate that the chemokine receptor Cxcr[1] promotes neutrophil clustering but is rapidly desensitized and internalized in response to gradients of its ligand (Cxcl8a) at wounds

  • Zebrafish larvae are ideally amenable to imaging and genetic manipulation, and express homologs of the human CXCL8 receptors CXCR1 (Cxcr1) and CXCR2 (Cxcr2)[26]

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Summary

Introduction

This occurs at the expense of global space exploration and the encounter of alternative signals nearby. We demonstrate that the chemokine receptor Cxcr[1] promotes neutrophil clustering but is rapidly desensitized and internalized in response to gradients of its ligand (Cxcl8a) at wounds. This is critical to allow transition to signaling through the chemokine receptor Cxcr[2], which recognizes Cxcl8b and promotes bidirectional motion. We show that this is required for sustained random motion and reverse migration that supports resolution of the response These findings provide a foundation for identifying receptors that mediate neutrophil dispersal in mammals and for directing chemoattractant drug discovery towards specific leukocyte trafficking patterns

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