Our bodies possess a sophisticated defense system against invading pathogens, and a major component of this system is white blood cells, also known as leukocytes. Among these, neutrophils are the most numerous type, serving as rapid responders to infection or injury. They are constantly searching for signs of infection and quickly migrate to sites of inflammation.
Neutrophils traditionally combat threats by engulfing and breaking down microorganisms through a process called phagocytosis. However, a unique and somewhat unexpected defense mechanism, Neutrophil Extracellular Traps (NETs), was identified in 2004. This discovery revealed that neutrophils can also release web-like structures composed of their own cellular material to trap and neutralize pathogens.
What Neutrophil Extracellular Traps Are and How They Form
Neutrophil Extracellular Traps (NETs) are web-like structures composed of decondensed chromatin (DNA and proteins) and various antimicrobial proteins. These intricate networks are expelled from neutrophils, forming a sticky mesh designed to ensnare and disarm invading microbes. Their primary components include DNA, structural proteins called histones, and specific granular proteins like myeloperoxidase (MPO) and neutrophil elastase (NE).
The formation of NETs, a process termed NETosis, involves a distinct series of cellular changes that are different from typical cell death pathways like apoptosis or necrosis. During NETosis, the neutrophil’s nucleus undergoes swelling, and the tightly packed chromatin within decondenses and expands. This decondensed chromatin then mixes with the contents of the neutrophil’s antimicrobial granules.
Following these internal rearrangements, the neutrophil’s cell membrane ruptures, leading to the expulsion of this web-like structure into the extracellular space. These DNA-protein traps are then released, ready to capture pathogens.
The Protective Role of NETs
NETs serve as a direct physical barrier, trapping and preventing the spread of various pathogens, including bacteria, fungi, viruses, and parasites. Their sticky, web-like architecture physically immobilizes microbes, concentrating them within the trap and limiting infection spread.
Beyond physical entrapment, NETs also concentrate and deliver an array of antimicrobial proteins directly onto ensnared pathogens. These proteins, including neutrophil elastase and myeloperoxidase, work to break down and neutralize microbial components. This combined action enhances the neutrophil’s ability to clear infections.
NETs also contribute to the broader immune response by activating other immune cells and aiding pathogen clearance. For example, they can interact with and influence the behavior of cells such as dendritic cells and T cells, helping to shape the adaptive immune response.
When NETs Turn Harmful: Disease Associations
While NETs offer protective benefits, their excessive or uncontrolled formation, or impaired clearance, can contribute to the development and progression of various diseases. When not properly regulated or removed, NET components can persist and incite damaging immune responses against the body’s own tissues.
In autoimmune diseases, NETs are increasingly recognized as contributors to the body mistakenly attacking its own tissues. For instance, in systemic lupus erythematosus (SLE) and rheumatoid arthritis, components of NETs can act as autoantigens, prompting the immune system to produce antibodies against them. This immune response leads to chronic inflammation and tissue damage characteristic of these conditions.
NETs also play a role in chronic inflammatory conditions. Their presence can exacerbate inflammation in diseases such as severe asthma, where they contribute to airway obstruction and tissue remodeling, or in pancreatitis, where they can intensify pancreatic tissue damage.
A harmful effect of NETs is their contribution to blood clot formation, a process known as thrombosis. In conditions like deep vein thrombosis or severe infections such as sepsis, NETs provide a scaffold that promotes platelet adhesion and activation, leading to the formation of clots. The DNA and histones within NETs can directly activate clotting pathways, increasing the risk of thrombotic events.
Furthermore, emerging research suggests a role for NETs in cancer progression. They can promote metastasis by creating a favorable microenvironment for tumor cells to grow and spread. NETs may also shield cancer cells from immune surveillance and contribute to drug resistance.