Neutrophils are the most numerous type of white blood cell, constituting about 50 to 70% of all circulating leukocytes. They serve as the immune system’s rapid-response team against invading pathogens. As a core component of the innate immune system, they provide a non-specific, immediate defense, particularly against bacteria and fungi. Produced constantly in the bone marrow (approximately \(10^{11}\) per day), neutrophils are highly mobile and short-lived. Their primary function is to quickly locate and neutralize threats before they can establish a foothold in the body’s tissues.
Physical Identity and Formation
Neutrophils are classified as polymorphonuclear leukocytes (PMNs) because their nucleus has a distinctive multi-lobed appearance, typically consisting of two to five segments connected by thin chromatin strands. This unique structure distinguishes them from other white blood cells, such as lymphocytes. When mature, these cells measure approximately 12 to 15 micrometers in diameter.
The cytoplasm is filled with specialized, enzyme-containing sacs called granules, which are responsible for their microbicidal capabilities. These granules are categorized into primary (azurophilic) and secondary (specific) types, each containing a different arsenal of compounds. Primary granules hold potent enzymes like myeloperoxidase and defensins, while secondary granules contain substances such as lactoferrin and components of the NADPH oxidase enzyme complex.
The production process, known as granulopoiesis, takes place in the bone marrow and involves the differentiation of hematopoietic stem cells. Once mature, the cells are released into the bloodstream where they circulate for a relatively short time, often no more than 72 hours. They then either migrate to tissues or undergo programmed cell death.
The Rapid Response: Migration to Infection Sites
When an infection or injury occurs, neutrophils must rapidly exit the bloodstream and enter the affected tissue, guided by chemical signaling. Damaged host cells and invading pathogens release signaling molecules like chemokines, such as Interleukin-8 (IL-8), which create a chemical gradient. Neutrophils sense this gradient and move toward the highest concentration of these signals through chemotaxis.
The process of leaving the blood vessel is known as extravasation. Initially, the neutrophil slows its speed by “rolling” along the inner surface of the blood vessel through temporary, selectin-dependent interactions. This rolling leads to a firmer “adhesion” to the endothelial wall, mediated by adhesion molecules called integrins.
The final step is diapedesis, where the highly polarized neutrophil squeezes itself through the endothelial cell barrier and the underlying basement membrane to reach the tissue. This transmigration can occur either between endothelial cells (paracellularly) or directly through the body of an endothelial cell (transcellularly). Once in the tissue, the neutrophil continues to migrate along the chemical gradient to reach the microbial threat.
Primary Methods of Pathogen Destruction
Once neutrophils arrive at the infection site, they employ three distinct mechanisms to destroy or neutralize pathogens. The most well-known method is phagocytosis, the process of engulfing a foreign particle. The neutrophil extends its membrane to surround the pathogen, internalizing it within a membrane-bound sac called a phagosome.
Following internalization, the phagosome fuses with the neutrophil’s granules to form a phagolysosome, an acidic compartment where the pathogen is destroyed. Destruction involves the rapid production of highly toxic reactive oxygen species (ROS), termed the “respiratory burst,” and the action of hydrolytic enzymes released from the granules. This oxygen-dependent killing mechanism is effective against many bacteria and fungi.
A second method is degranulation, the deliberate release of granular contents into the extracellular space. This mechanism is employed when a pathogen is too large to be engulfed or to combat a high concentration of extracellular microbes. The neutrophil releases antimicrobial peptides, proteins, and enzymes, such as myeloperoxidase and neutrophil elastase, to destroy the threat outside the cell.
The third primary defense mechanism is the formation of Neutrophil Extracellular Traps (NETs), a process called NETosis. In this unique form of cell death, the neutrophil intentionally expels a web-like structure composed of decondensed nuclear DNA complexed with antimicrobial proteins. These sticky NETs physically trap and immobilize pathogens, preventing their spread and concentrating antimicrobial components.
When Neutrophils Malfunction
Disorders involving neutrophils arise from abnormal numbers of circulating cells or functional impairment in their killing mechanisms. Neutropenia describes a condition where the count of circulating neutrophils is abnormally low, which compromises the immune system’s defense. This deficit results in increased susceptibility to severe and recurrent bacterial and fungal infections.
Conversely, neutrophilia is characterized by an abnormally high number of neutrophils in the blood, typically associated with acute inflammation, severe infection, or physical stress. While often a response to infection, persistent neutrophilia can also be a sign of underlying conditions, such as certain blood cancers. The excessive number of active cells can sometimes contribute to tissue damage due to the indiscriminate release of their toxic contents.
Beyond count abnormalities, functional defects can render neutrophils ineffective even if their numbers are normal. Chronic Granulomatous Disease (CGD) is an example where neutrophils successfully engulf pathogens but fail to kill them due to a defective respiratory burst. In CGD, the necessary reactive oxygen species are not produced, allowing microbes to survive inside the phagolysosome, which leads to chronic infections and the formation of inflammatory masses called granulomas.