Neutrophil migration in infection and wound repair: going forward in reverse

Abstract

Neutrophil migration and its role during inflammation has been the focus of increased interest in the past decade. Advances in live imaging and the use of new model systems have helped to uncover the behaviour of neutrophils in injured and infected tissues. Although neutrophils were considered to be short-lived effector cells that undergo apoptosis in damaged tissues, recent evidence suggests that neutrophil behaviour is more complex and, in some settings, neutrophils might leave sites of tissue injury and migrate back into the vasculature. The role of reverse migration and its contribution to resolution of inflammation remains unclear. In this Review, we discuss the different cues within tissues that mediate neutrophil forward and reverse migration in response to injury or infection and the implications of these mechanisms to human disease.

Figure 1. The phases of neutrophil recruitment

The recruitment of neutrophils to a site of damage occurs in several phases. Damage-associated molecular patterns (DAMPs) are released at a tissue injury site and promote the release of hydrogen peroxide (H₂O₂) and direct the recruitment of early-arriving neutrophils through the SRC family kinase LYN (a). DAMPs also induce the production of CXC-chemokine ligand 8 (CXCL8) family chemokines and leukotrienes from surrounding tissue cells to further recruit neutrophils (b). Early-arriving neutrophils are then themselves activated to both directly and indirectly promote further secretion of CXCL8 family chemokines and leukotriene B4 (LTB4) to induce neutrophil recruitment from the circulation and amplification of the response (c). In an infection, extra layers of signalling exist to prolong and amplify neutrophil infiltration, including the release of pathogen-associated molecular patterns (PAMPs) and the involvement of other recruited immune cells, such as macrophages, dendritic cells (DCs) and T cells (d). IL, interleukin; PI3K, phosphoinositide 3-kinase; TNF, tumour necrosis factor.

Figure 2. Mechanisms that may be involved in neutrophil reverse migration

Several models for reverse migration have been developed: in vitro microfluidic assays or transwell assays (a), larval zebrafish wounding (b), and mouse ischemia-reperfusion injury to model reverse transendothelial migration (rTEM) (c). These studies have reported mechanisms that regulate both neutrophil reverse migration in interstitial tissues and rTEM. a. Chemoattractants, such as CXC-chemokine ligand 8 (CXCL8), can act as chemorepellents at high concentrations in vitro, referred to as fugetaxis (i). Reverse neutrophil transmigration through endothelial cell monolayers has been reported; reverse transmigrated neutrophils have been characterised by high expression of intercellular adhesion molecule 1 (ICAM1) and low expression of CXC-chemokine receptor 1 (CXCR1) (ii). In vitro analysis in microfluidics has identified factors that regulate neutrophil forward and reverse migration (iii). The pro-resolving lipid mediator lipoxin A4 (LX4A) induces neutrophil reverse migration whereas zymosan induces neutrophil trapping. b. The reverse migration and rTEM of neutrophils has been visualized in larval zebrafish tail wounds using photoconversion (i). The activation of hypoxia-inducible factor 1α (HIF1α) in zebrafish neutrophils inhibits neutrophil reverse migration (ii), whereas the migration of macrophages to the wound via reactive oxygen species (ROS)-SRC family kinase (SFK) signalling and their direct interaction with neutrophils promotes neutrophil reverse migration (iii). c. A mouse ischemia-reperfusion injury model is used to model neutrophil rTEM or “hesitant” TEM. In this model, junctional adhesion molecule C (JAM-C) on endothelial cells modulates “complete” TEM and leukotriene B4 (LTB4) induces neutrophil elastase expression, which cleaves JAM-C, leading to an increase in rTEM (i, adapted from Colom et al, Immunity, 2015). Increased rTEM in this model leads to higher numbers of neutrophils with rTEM markers (ICAM1^hi CXCR1^low) at secondary sites such as the lungs (ii).