Neutrophil Migration: Importance for Infection and Wound Repair

Neutrophils are a crucial part of the immune system, acting as first responders to infection and injury. Their rapid migration through blood vessels and tissues is essential for eliminating pathogens and promoting healing.

Understanding how neutrophils move provides insight into their role in immunity and tissue repair.

Key Signals That Guide Movement

Neutrophil migration is directed by chemical signals that guide them to infection or injury sites. These signals, known as chemotactic factors, create a gradient that neutrophils detect and follow through chemotaxis. Potent attractants include bacterial formyl peptides like N-formyl-methionyl-leucyl-phenylalanine (fMLP) and host-derived molecules such as interleukin-8 (IL-8), leukotriene B4 (LTB4), and complement component C5a.

Neutrophils rely on specialized receptors in their membranes to sense and respond to these signals. G-protein-coupled receptors (GPCRs) detect chemotactic molecules and trigger intracellular signaling cascades that reorganize the cytoskeleton. This enables the cell to extend pseudopodia toward the highest concentration of the chemotactic signal. Actin polymerizes at the leading edge, while myosin contraction propels the cell forward, allowing navigation through complex tissues.

Adhesion molecules on endothelial cells and the extracellular matrix further refine neutrophil movement. Selectins and integrins mediate interactions with blood vessel walls, ensuring controlled migration. Inflammatory signals upregulate these adhesion molecules, promoting neutrophil recruitment. Once out of circulation, neutrophils use integrins to interact with fibronectin, laminin, and other extracellular components for efficient tissue traversal.

Steps Of Migration

Neutrophil migration from the bloodstream into tissues follows a structured sequence that ensures efficient movement while maintaining vascular integrity. This process involves rolling, tight adhesion, and transendothelial migration.

Rolling

Neutrophils first slow down and transiently adhere to the endothelial lining of blood vessels through selectins, adhesion molecules expressed on endothelial cells and neutrophils. Endothelial cells upregulate P-selectin and E-selectin in response to inflammatory signals like tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). Neutrophils express L-selectin, facilitating weak, reversible binding.

Selectin-ligand interactions create a tethering effect, causing neutrophils to roll along the endothelium rather than being carried away by blood flow. This motion allows them to scan for signals promoting firmer adhesion. The strength and duration of rolling interactions depend on blood flow shear stress and selectin density. Deficiencies in selectins or their ligands can impair neutrophil recruitment, delaying responses to infection or injury.

Tight Adhesion

After rolling, neutrophils firmly anchor to the vessel wall through integrins, which undergo conformational changes to increase binding affinity. Neutrophils express β2 integrins, such as lymphocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1), which interact with intercellular adhesion molecules (ICAM-1 and ICAM-2) on endothelial cells.

Integrins are activated by chemokines like IL-8, which shift them from a low-affinity to a high-affinity state, strengthening adhesion. This firm attachment prevents neutrophils from being dislodged by blood flow and prepares them for transendothelial migration. Mutations affecting β2 integrins, such as in leukocyte adhesion deficiency (LAD) syndromes, impair adhesion and migration, highlighting the significance of this step.

Transendothelial Migration

Once firmly attached, neutrophils exit the bloodstream through transendothelial migration, or diapedesis. This occurs either via the paracellular route, where they pass between endothelial cells, or the transcellular route, where they migrate directly through endothelial cells. The paracellular route is more common and involves temporary disruption of endothelial junctions, regulated by proteins like platelet endothelial cell adhesion molecule-1 (PECAM-1), junctional adhesion molecules (JAMs), and CD99.

Neutrophils extend lamellipodia to navigate endothelial gaps, while endothelial cells assist by retracting junctions. They then degrade the basement membrane using matrix metalloproteinases (MMPs) to facilitate passage. The transcellular route, though less frequent, allows neutrophils to pass through endothelial cells without disrupting junctions. Intravital microscopy studies show that the choice of migration route depends on endothelial cell type and inflammatory conditions.

After crossing the endothelium, neutrophils move through the extracellular matrix, guided by chemotactic signals, ensuring timely arrival at infection or injury sites.

Role In Infection

Neutrophils are key players in infection control, rapidly detecting and neutralizing microbial threats. Pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), recognize microbial structures like lipopolysaccharides on Gram-negative bacteria or peptidoglycan in Gram-positive species. These receptors trigger intracellular pathways that enhance antimicrobial responses, including the release of reactive oxygen species (ROS) through the NADPH oxidase complex. ROS, such as superoxide anions and hydrogen peroxide, disrupt microbial membranes and inhibit metabolism, weakening pathogens before engulfment.

Neutrophils also deploy antimicrobial peptides and enzymes stored in cytoplasmic granules. Myeloperoxidase catalyzes hypochlorous acid production, a potent microbicidal agent, while neutrophil elastase and cathepsin G degrade bacterial proteins and virulence factors. Upon encountering pathogens, neutrophils release these contents into phagosomes, dismantling internalized microbes. For extracellular pathogens, they expel granule contents into the surrounding environment, limiting bacterial proliferation.

Another pathogen-eliminating strategy is neutrophil extracellular traps (NETs), chromatin fibers embedded with antimicrobial proteins. NETs immobilize bacteria, fungi, and viruses, preventing their spread while exposing them to toxic enzymes. NETosis, triggered by bacterial endotoxins or inflammatory cytokines, is effective in pathogen containment but can also contribute to tissue damage and autoimmune conditions.

Importance In Wound Repair

Neutrophils aid wound repair by clearing damaged tissue and facilitating regeneration. Upon injury, disrupted vasculature releases damage-associated molecular patterns (DAMPs), signaling neutrophils to infiltrate the site. They remove cellular debris and necrotic material through phagocytosis and the release of degradative enzymes like matrix metalloproteinases (MMPs), which break down damaged extracellular matrix components and prevent excessive fibrosis.

As neutrophils clear debris, they secrete pro-resolving mediators that transition inflammation to tissue repair. Lipid-derived molecules like lipoxins and resolvins suppress further neutrophil recruitment while enhancing apoptotic cell clearance by macrophages. This shift prevents prolonged inflammation, linked to chronic wounds in conditions like diabetes. Neutrophil-derived vascular endothelial growth factor (VEGF) promotes angiogenesis, ensuring new tissue receives adequate oxygen and nutrients.

Interactions With Immune Cells

Neutrophils interact with other immune cells, shaping inflammation and influencing infection resolution and tissue repair. These interactions involve direct contact and signaling molecules that modulate immune activity.

A key interaction occurs with macrophages, which play roles in inflammation and repair. As neutrophils complete their antimicrobial functions, they undergo apoptosis and are engulfed by macrophages in efferocytosis. This clearance prevents excessive inflammation and shifts macrophages toward an anti-inflammatory phenotype, promoting tissue resolution.

Neutrophils also communicate with dendritic cells, influencing adaptive immunity by modulating antigen presentation. By releasing cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-12 (IL-12), they enhance dendritic cell maturation and T cell activation, linking innate and adaptive immunity. Additionally, interactions with natural killer (NK) cells enhance host defense against intracellular pathogens. Neutrophils release interferon-gamma (IFN-γ) and other signals that boost NK cell cytotoxicity, improving responses against virus-infected or malignant cells.

These interactions highlight neutrophils’ broader role beyond first responders, demonstrating their influence on immune dynamics in infection and tissue healing.