Neutrophils are white blood cells acting as the immune system’s first line of defense. To reach a site of inflammation, they must exit the bloodstream. This process begins with neutrophil rolling, where the cell slows its pace and tumbles along the inner wall of a blood vessel. This action is the initial step that allows the neutrophil to stop and move into the affected tissue.
The Inflammatory Signal for Action
When tissues are damaged or invaded by bacteria, the body initiates an inflammatory response. Damaged cells and resident immune cells, like macrophages, release chemical signals called cytokines and chemokines. These substances, including Interleukin-8 (IL-8), alert the immune system to the problem.
These chemical messengers reach nearby small blood vessels, triggering a change in the endothelial cells that form the inner lining. In response, the endothelial cells display specific adhesion molecules on their surface. This makes the vessel wall stickier for passing neutrophils, ensuring they slow down precisely where needed.
The concentration of these signals is highest at the source of injury, creating a chemical gradient. Neutrophils have receptors to detect these gradients, guiding their movement in a process called chemotaxis. This signaling sets the stage for the initial interaction with the vessel wall that leads to rolling.
The Process of Rolling
Inside blood vessels, blood flows at high speeds, normally sweeping neutrophils along without interacting with the vessel walls. In an area of inflammation, a neutrophil makes contact with the modified endothelial surface. It forms transient, weak bonds that are quickly made and broken. This series of rapid attachments causes the cell to tumble along the vessel wall in a jerky, stop-and-go motion.
This rolling dramatically slows the neutrophil’s velocity compared to the free-flowing cells in the center of the bloodstream. This deceleration is an intermediate step that gives the neutrophil time to sense its environment and detect other signals that will guide its next actions. Without this initial slowing, the cell would be swept past the site of inflammation, unable to respond.
Molecules That Mediate Rolling
Neutrophil rolling is orchestrated by molecules known as selectins and their corresponding carbohydrate-based ligands. Following an inflammatory signal, endothelial cells express two main types of selectins on their surface: P-selectin and E-selectin. P-selectin can be moved to the cell surface within minutes, while E-selectin expression takes a few hours.
Neutrophils, in turn, continuously display a ligand on their surface called P-selectin glycoprotein ligand-1 (PSGL-1). This molecule is structured to bind with both P-selectin and E-selectin on the activated endothelium. The interaction between the selectins on the vessel wall and PSGL-1 on the neutrophil creates the temporary tethers that facilitate rolling. L-selectin, another selectin on the neutrophil’s surface, also contributes by binding to endothelial ligands.
These bonds are characterized by their low affinity and rapid dissociation rates, meaning they form and break away easily. This allows the neutrophil to roll rather than coming to a complete halt. The force of the flowing blood is sufficient to break these weak connections, causing the cell to tumble forward until new bonds form with the next available selectins.
From Rolling to Firm Adhesion
As the neutrophil tumbles along the endothelial surface, it is exposed to chemokines, like IL-8, that are bound to the vessel wall. The binding of these chemokines to receptors on the neutrophil’s surface triggers a new cascade of intracellular events.
This activation signal induces a conformational change in a different class of adhesion molecules on the neutrophil called integrins. In their resting state, these integrins have a low affinity for their binding partners. The chemokine signal rapidly switches them to a high-affinity state, activating them to bind tightly.
Once activated, these high-affinity integrins lock onto their corresponding molecules on the endothelial cell surface, primarily Intercellular Adhesion Molecule-1 (ICAM-1). This bond is much stronger and more stable than the selectin-mediated tethers. This brings the rolling neutrophil to a complete stop, a state known as firm adhesion. From this stationary position, the neutrophil can then begin squeezing between the endothelial cells to exit the bloodstream.
Consequences of Dysfunctional Rolling
The coordination of neutrophil rolling is part of the innate immune response, and its failure can have severe health consequences. Genetic disorders impairing this process prevent neutrophils from reaching sites of infection, leaving the body vulnerable to bacterial assaults.
An example of this is Leukocyte Adhesion Deficiency Type II (LAD-II). This rare genetic condition is caused by a defect in the synthesis of the carbohydrate structures that form the ligands for selectins. Without these functional ligands, neutrophils cannot form the initial weak tethers with the blood vessel wall.
As a result, the neutrophils are unable to slow down and roll along the endothelium. They are swept along in the bloodstream, bypassing the inflamed tissues where they are needed. Patients with LAD-II suffer from recurrent, life-threatening bacterial infections because their “first responder” immune cells cannot get to the scene of the emergency. This condition underscores how this rolling action is a necessary step in mounting an effective defense against pathogens.