Neutrophils are the most abundant type of white blood cell, acting as the rapid first responders of the innate immune system. These cells patrol the bloodstream, ready to be deployed instantly to sites of injury or infection, particularly those caused by bacteria and fungi. Their presence is a defining feature of acute inflammation, where they arrive in massive numbers to contain and neutralize invading pathogens.
Identity and Origin of Neutrophils
Neutrophils belong to a category of white blood cells known as granulocytes, characterized by enzyme-filled granules within their cytoplasm. They are also referred to as polymorphonuclear leukocytes (PMNs) due to their unique, multi-lobed nucleus. In humans, neutrophils constitute 50 to 70 percent of all circulating leukocytes.
The continuous generation of these specialized cells occurs through hematopoiesis within the bone marrow. The body produces approximately \(10^{11}\) new neutrophils every day to meet the constant demand. Once released into the circulation, neutrophils have a notably short lifespan, generally surviving for only a few hours to a day before clearance.
Locating the Threat: Chemotaxis and Migration
The speed and accuracy of the neutrophil response are governed by a chemical guidance system known as chemotaxis. When tissue damage or microbial invasion occurs, local cells and pathogens release specific chemical signals, including chemokines like Interleukin-8 (IL-8) and complement components such as C5a. Neutrophils sense these molecular gradients and are directed toward the highest concentration.
To reach the site of infection, neutrophils must transition from the bloodstream into the affected tissue, a process called extravasation. This journey begins with the cell loosely rolling along the inner surface of blood vessel walls, mediated by adhesion molecules called selectins. This is followed by firm adhesion, where molecules on the neutrophil surface, such as integrins, tightly bind to receptors on the endothelial cells lining the blood vessel. Finally, the neutrophil squeezes between the endothelial cells to enter the tissue space and begin its search for microbes.
The Arsenal: Mechanisms of Microbial Destruction
Once they arrive at the site of infection, neutrophils deploy a powerful and varied set of antimicrobial strategies to neutralize pathogens. The three primary methods of destruction are phagocytosis, degranulation, and the formation of Neutrophil Extracellular Traps (NETs). These mechanisms can be used sequentially or simultaneously depending on the nature of the threat.
Phagocytosis
Phagocytosis is the process of physically engulfing the target microbe, internalizing it within a membrane-bound compartment called a phagosome. The phagosome then fuses with the neutrophil’s granules, creating a highly toxic environment to kill the trapped pathogen. A central part of this intracellular killing is the respiratory burst, an enzyme reaction catalyzed by NADPH oxidase that produces reactive oxygen species (ROS). These potent oxygen molecules chemically destroy the ingested bacteria or fungi.
Degranulation
Degranulation involves the release of pre-formed antimicrobial proteins and enzymes stored in the cell’s cytoplasmic granules. These substances, which include myeloperoxidase (MPO) and defensins, can be discharged directly into the phagosome or released into the extracellular space. Releasing these potent enzymes externally helps to break down pathogens too large to be engulfed or to act in concert with other defense mechanisms.
Neutrophil Extracellular Traps (NETs)
The final, distinct method is NETosis, a unique form of programmed cell death where the neutrophil sacrifices itself to create a physical trap. The cell expels its decondensed nuclear material—a mesh of DNA decorated with antimicrobial proteins like MPO and elastase. This sticky, web-like structure, known as a Neutrophil Extracellular Trap (NET), physically snares and concentrates microbes outside the cell, preventing their spread.
Signaling the End: Apoptosis and Inflammation Resolution
Following the successful clearance of pathogens, the activity of neutrophils must be terminated to prevent damage to surrounding healthy host tissue. The lifespan of a neutrophil is strictly controlled, and the cell is programmed to undergo a controlled form of cell death called apoptosis. This process ensures that the neutrophil’s potent, toxic contents are safely contained.
The apoptotic neutrophil then displays specific signals that mark it for disposal by nearby macrophages. This clean-up process, termed efferocytosis, involves the macrophage safely engulfing and digesting the dying neutrophil. The efficient removal of apoptotic neutrophils actively promotes the resolution of acute inflammation. By consuming the dead neutrophils, macrophages are often polarized toward an anti-inflammatory state, preventing the transition to chronic inflammation.