Signal integration in forward and reverse neutrophil migration: Fundamentals and emerging mechanisms

Highlights

• Neutrophil reverse migration has emerged as a critical component of inflammation resolution.

• In wounds, neutrophils integrate proinflammatory recruitment and retention signals and anti-inflammatory dispersal signals..

• Emerging molecular players and pathways provide mechanistic insights into these complex signaling decisions.

• A more holistic model of signal integration in migrating cells that encompasses forward and reverse migration is developing.

Abstract

Neutrophils migrate to sites of tissue damage, where they protect the host against pathogens. Often, the cost of these neutrophil defenses is collateral damage to healthy tissues. Thus, the immune system has evolved multiple mechanisms to regulate neutrophil migration. One of these mechanisms is reverse migration — the process whereby neutrophils leave the source of inflammation. In vivo, neutrophils arrive and depart the wound simultaneously — indicating that neutrophils dynamically integrate conflicting signals to engage in forward and reverse migration. This finding is seemingly at odds with the established chemoattractant hierarchy in vitro, which places wound-derived signals at the top. Here we will discuss recent work that has uncovered key players involved in retaining and dispersing neutrophils from wounds. These findings offer the opportunity to integrate established and emerging mechanisms into a holistic model for neutrophil migration in vivo.

Introduction

Neutrophils are often the first immune cells to arrive at sites of injury and infection. There, they mount a potent defense response that must be tightly regulated to limit collateral damage to the host [1]. Indeed, excessive or inappropriate neutrophilic inflammation can tip the balance from host protection to autoimmunity and tissue damage [1]. Neutrophils and other leukocytes exhibit complex decision-making within interstitial tissues in response to various cues to maintain tissue homeostasis and enable tissue repair.

An example of this complex decision-making is the neutrophil response to sterile tissue injury. Until recently, neutrophil recruitment to injury sites was considered unidirectional, with neutrophils undergoing apoptosis and subsequent clearance by macrophages at the wound [2]. However, it is increasingly evident that a subset of neutrophils leave inflamed tissues and re-enter the circulation [3, 4, 5, 6]. The reverse migration and reverse transmigration of neutrophils into the vasculature have now been described in zebrafish, mice, and humans, suggesting they play a critical role in local inflammation resolution [3, 4, 5, 6]. Indeed, in addition to clearing apoptotic neutrophils, macrophages have also been reported to repel wound-associated neutrophils [7,8] or ‘cloak’ sites of sterile damage, thereby limiting chemoattractant signaling and neutrophil inflammation [9•].

The mechanism underlying the prioritization between tissue damage cues and reverse migration is not fully understood. In part, this is due to the daunting complexity of the physical and chemical landscape neutrophils encounter in vivo [10,11]. Furthermore, the signals that regulate reverse migration are not well defined. Recent work in vivo and in vitro has just begun to uncover some of the molecular players and signaling pathways that regulate reverse migration. Here, we discuss how neutrophils prioritize chemoattractant signals in vitro and more complex in vivo contexts and discuss how these mechanisms may provide insight into the complex prioritization needed to reverse migrate and resolve a local response.