Neutrophils – Definition, structure, count, range, functions

Neutrophils are a type of white blood cell that play a vital role in the immune system. They are the most abundant and the first to arrive at the site of infection, where they engulf and destroy bacteria and other foreign invaders. Neutrophils are also involved in inflammation, wound healing and tissue remodeling.

Neutrophils are classified as granulocytes because they have granules in their cytoplasm that contain enzymes and proteins that help them fight infection. They are also called polymorphonuclear leukocytes (PMNs) because they have a nucleus with multiple lobes.

Neutrophils are produced in the bone marrow from stem cells and circulate in the blood for a few hours before migrating into the tissues. They have a short lifespan of only a few days, after which they die by a process called apoptosis or programmed cell death.

Neutrophils can be divided into two subtypes: neutrophil-killers and neutrophil-cagers. Neutrophil-killers are the ones that directly attack and kill bacteria by phagocytosis (cell eating) and secretion of antimicrobial substances. Neutrophil-cagers are the ones that transport bacteria to the site of infection and trap them in extracellular traps called neutrophil extracellular traps (NETs).

Neutrophils are part of the innate immune system, which means they can recognize and respond to common pathogens without prior exposure or memory. They can also interact with other cells of the immune system, such as macrophages, dendritic cells and lymphocytes, to coordinate a more effective immune response.

Neutrophils are essential for fighting infection and maintaining health, but they can also cause damage to the host tissues if they are activated inappropriately or excessively. Disorders of neutrophil function can result in increased susceptibility to infection (neutropenia) or chronic inflammation (neutrophilia).

In this article, we will discuss the structure, count, range and functions of neutrophils in more detail. We will also look at some of the causes and consequences of abnormal neutrophil levels in the blood. Finally, we will watch a video lecture by Thomas Underhill on the mechanisms of neutrophil action.

Neutrophils are mostly circular cells that range in size from 12 to 15 micrometers (µm) in diameter. In humans, the average size of a neutrophil is about 8 µm. However, their shape changes into amoeboid when they are activated by an infection or inflammation. This allows them to extend their pseudopodia (false feet) to move and attack the invaders.

Neutrophils have a characteristic multi-lobed nucleus with 3 to 5 lobes connected by thin strands of chromatin. The number of lobes increases as the neutrophil matures. The nucleolus, which is the site of ribosome synthesis, is present in young neutrophils but disappears in mature ones. The nucleus of a neutrophil is often described as having a "string of beads" appearance.

The cytoplasm of neutrophils contains many granules that stain purple with a dye called Wright`s stain. These granules are classified into two types: primary (or azurophilic) and secondary (or specific) granules. Primary granules are larger and more numerous than secondary granules. They contain enzymes and proteins that help kill and digest the microbes that are phagocytosed by the neutrophil. Some of these substances are myeloperoxidase, lysozyme, defensins, and elastase. Secondary granules are smaller and less dense than primary granules. They contain enzymes and proteins that help modulate the inflammatory response and tissue repair. Some of these substances are lactoferrin, collagenase, gelatinase, and alkaline phosphatase.

Other cytoplasmic organelles that are present in neutrophils include mitochondria, Golgi complex, endosomes, and lysosomes. However, these organelles are sparse and poorly developed compared to other cells. This is because neutrophils rely mainly on glycolysis for energy production and do not need a lot of protein synthesis or membrane trafficking. The endoplasmic reticulum, which is involved in protein synthesis and folding, is absent in neutrophils.

Absolute Neutrophil Count (ANC) is the test to measure the number of neutrophils and other granulocytes (collectively termed polymorphonuclear cells) present in a blood sample. This test usually detects the total number of white blood cells which includes both mature and immature neutrophils. The neutrophil blood count breakdown neutrophils into two categories as segmented or mature neutrophils and immature neutrophils or bands. The neutrophil count is commonly conducted to detect abnormalities related to the increase or decrease in the number of neutrophils. The abnormal count of neutrophils is often associated with various medical conditions, which makes this test an essential part of the laboratory examination of many diseases.

The formula for calculation of absolute neutrophil count is given below:

$$ANC = WBC \times (\% \text{mature neutrophils} + \% \text{immature neutrophils})$$

Or

$$ANC= \text{Absolute mature neutrophils} + \text{absolute immature neutrophils}$$

This test is performed to detect the presence of different organisms in the bloodstream and also to detect if the immune system is working correctly. ANC is usually performed as a part of the complete blood count to measure the count of different blood cells.

The normal range of ANC count in adults is 1500-8000 cells/mm3. However, this range may vary depending on age, gender, ethnicity, and other factors. Therefore, it is important to consult a doctor for the interpretation of the results.

A low ANC count indicates a condition called neutropenia, which means that the body has a reduced ability to fight infections. A high ANC count indicates a condition called neutrophilia, which means that the body has an increased inflammatory response or an infection.

Some of the factors that can affect the ANC count are:

• Medications: Some drugs, such as chemotherapy, antibiotics, anticonvulsants, and anti-inflammatory drugs, can lower or raise the ANC count.
• Infections: Bacterial, viral, fungal, or parasitic infections can cause an increase or decrease in the ANC count.
• Inflammation: Conditions that cause inflammation, such as rheumatoid arthritis, Crohn`s disease, ulcerative colitis, or lupus, can affect the ANC count.
• Bone marrow disorders: Diseases that affect the production or function of bone marrow cells, such as leukemia, aplastic anemia, myelodysplastic syndrome, or myelofibrosis, can alter the ANC count.
• Lifestyle factors: Smoking, alcohol consumption, stress, exercise, and diet can also influence the ANC count.

The ANC test is a simple and quick procedure that involves drawing a small amount of blood from a vein in the arm. The blood sample is then sent to a laboratory for analysis. The results are usually available within a few hours or days.

The ANC test is a useful tool for diagnosing and monitoring various health conditions. However, it is not a definitive test and should be interpreted along with other clinical findings and symptoms. Therefore, it is important to consult a doctor for any questions or concerns regarding the ANC test.

The number of neutrophils in the blood might differ from person to person as it is affected by various factors like age and the environment. However, the following is considered to be the normal range of neutrophil count.

In terms of cell count:

• The normal range of ANC count in adults: 1500-8000 cells/mm3 .
• The normal range of mature/ segmented neutrophils: 2500-6000 cells/mm3.
• The normal range of immature neutrophils: 0-500 cells/mm3.

In terms of percentage of the WBC:

• The normal range of ANC count in adults: 40-45 %.
• The normal range of mature/ segmented neutrophils: 40-60%.
• The normal range of immature neutrophils: 0-5%.

The neutrophil count is usually measured by a blood test called an absolute neutrophil count (ANC) that calculates the number of neutrophils and other granulocytes in a blood sample. The ANC is performed as a part of the complete blood count (CBC) that evaluates the composition and proportion of different blood cells. The ANC is used to check for signs of infection, inflammation, and certain cancers like leukemia and lymphoma .

The formula for calculation of absolute neutrophil count is given below:

$$ANC = (Total WBCs \times \% Neutrophils) + (Total WBCs \times \% Bands)$$

Or

$$ANC= Absolute mature neutrophils + absolute immature neutrophils$$

When the level of neutrophils in the blood is lower than normal, it is called neutropenia. The normal range of neutrophils for adults is about 1500 to 8000 cells per microliter of blood. Mild neutropenia is when the count is between 1000 and 1500 cells per microliter. Moderate neutropenia is when the count is between 500 and 1000 cells per microliter. Severe neutropenia is when the count is below 500 cells per microliter.

Neutropenia can be caused by various factors that affect the production, destruction or storage of neutrophils in the bone marrow or blood. Some of the common causes are :

• Chemotherapy: This is one of the most frequent causes of neutropenia, as chemotherapy drugs can damage the bone marrow and reduce the number of white blood cells, including neutrophils.
• Infections: Certain viral, bacterial or fungal infections can impair the bone marrow function or cause neutrophils to be used up faster than they can be replaced. Examples of infections that can cause neutropenia are hepatitis, tuberculosis, HIV/AIDS, sepsis and chickenpox.
• Medications: Some drugs can interfere with the production or survival of neutrophils, either as a side effect or an allergic reaction. Examples of such drugs are antibiotics, antivirals, anti-inflammatory drugs, antipsychotics and drugs for irregular heart rhythms.
• Autoimmune diseases: Some conditions that cause the immune system to attack healthy cells can also target neutrophils and destroy them. Examples of such conditions are lupus, rheumatoid arthritis and granulomatosis with polyangiitis.
• Bone marrow disorders: Some diseases that affect the bone marrow can reduce its ability to produce blood cells, including neutrophils. Examples of such diseases are aplastic anemia, myelodysplastic syndromes, leukemia and myelofibrosis.
• Vitamin deficiencies: Lack of certain vitamins, especially vitamin B12 and folate, can impair the maturation and division of blood cells, including neutrophils.
• Spleen disorders: The spleen is an organ that filters the blood and removes old or damaged blood cells, including neutrophils. If the spleen is enlarged or overactive (hypersplenism), it can remove too many neutrophils from the circulation.
• Genetic conditions: Some inherited disorders can affect the development or function of neutrophils from birth. Examples of such disorders are Kostmann`s syndrome (a rare condition that causes very low production of neutrophils), cyclic neutropenia (a condition that causes periodic drops in neutrophil levels) and benign ethnic neutropenia (a condition that causes lower-than-average neutrophil levels in some ethnic groups without increasing the risk of infection).

Neutropenia can increase the risk of infections, especially those affecting the skin and mucous membranes. People with neutropenia may not have any symptoms until they develop an infection. Some signs of infection are fever, chills, sore throat, mouth ulcers, skin rashes, abscesses and wounds that do not heal .

Neutropenia can be diagnosed by a blood test called a complete blood count (CBC), which measures the number and types of blood cells in a sample. A bone marrow biopsy may also be done to examine the source and cause of neutropenia .

The treatment of neutropenia depends on its cause and severity. Mild cases may not require any treatment, while moderate to severe cases may need antibiotics to prevent or treat infections, growth factors to stimulate the bone marrow to produce more neutrophils, transfusions of healthy neutrophils from a donor or bone marrow transplantation .

People with neutropenia can take some steps to prevent infections, such as maintaining good hygiene, avoiding contact with people who are sick, cleaning and covering any cuts or scrapes, avoiding raw or poorly cooked foods and pasteurized dairy products and consulting their doctor before taking any medications .

When the level of neutrophils is greater than 8000 cells/mm3, it is considered a high neutrophil level. This condition is termed neutrophilia. Neutrophilia might range from mild, occasional neutrophilia to a more severe condition, often termed neutrophil leukocytosis.

Because neutrophils are a part of the immune system, an increase in the neutrophil count is primarily caused by a bacterial infection, but the increased levels are also caused by other factors. The causes of the high neutrophil count are:

• The most common cause of neutrophilia is a bacterial infection, especially pyogenic infections resulting in inflammation. Examples of such infections are pneumonia, meningitis, appendicitis, and cellulitis. Bacterial infections stimulate the production and release of neutrophils from the bone marrow to fight the invading pathogens.
• Besides, increased neutrophil count is also observed during inflammation, usually after heart attacks or burns. Inflammation triggers the release of cytokines and chemokines that attract neutrophils to the site of injury or damage. Neutrophils then help in clearing the debris and repairing the tissue.
• An increased concentration of cortisol and adrenaline hormones and the ingestion of some drugs like prednisone also cause more neutrophils to enter the bloodstream. These hormones and drugs suppress the activity of lymphocytes and eosinophils, which normally regulate the number of neutrophils in circulation. As a result, more neutrophils are available to respond to stress or infection.
• Neutrophilia is also observed as a result of malignancy like leukemia. Leukemia is a type of cancer that affects the blood cells, especially the white blood cells. In some cases, leukemia causes an abnormal proliferation of immature neutrophils that crowd out the normal blood cells. This leads to a high neutrophil count along with other symptoms like anemia, bleeding, and infection.
• Surgical procedures, including splenectomy and appendicitis, are also known to increased neutrophil count. Splenectomy is the removal of the spleen, which is an organ that filters the blood and removes old or damaged blood cells. Without the spleen, more neutrophils remain in circulation and may cause an exaggerated immune response. Appendicitis is the inflammation of the appendix, which is a small pouch attached to the large intestine. Appendicitis can cause a bacterial infection that triggers neutrophilia.

A high neutrophil count can indicate an acute or chronic infection or inflammation that needs medical attention. However, it can also be a normal response to stress or exercise. Therefore, it is important to consider other factors like symptoms, medical history, and other blood tests before diagnosing a condition based on neutrophil count alone.

Neutrophils are the most abundant type of white blood cell in humans, and they play an important role in innate immunity. Their primary function is to prevent infections in the body by engulfing and destroying invading pathogens .

Neutrophils are constantly circulating in the blood, looking for signs of infection or injury. When they encounter a foreign particle or microorganism, they adhere to it and extend their pseudopodia (false feet) to surround it. This process is called phagocytosis.

Once the neutrophil has engulfed the pathogen, it forms a phagosome (a vesicle containing the pathogen) inside its cytoplasm. The phagosome then fuses with lysosomes (organelles containing digestive enzymes) and granules (organelles containing antimicrobial proteins) to form a phagolysosome. The enzymes and proteins inside the phagolysosome break down and kill the pathogen.

Some of the antimicrobial proteins that neutrophils secrete are:

• Defensins: Small peptides that can disrupt the membranes of bacteria and fungi.
• Lysozyme: An enzyme that can degrade the cell walls of bacteria.
• Lactoferrin: A protein that can bind iron and deprive bacteria of this essential nutrient.
• Myeloperoxidase: An enzyme that can produce reactive oxygen species (ROS) that can damage the DNA, proteins, and lipids of bacteria.

Neutrophils can also release some of their granules into the extracellular space to create a net-like structure called a neutrophil extracellular trap (NET). NETs can trap and kill bacteria, fungi, and parasites by exposing them to high concentrations of antimicrobial proteins and ROS.

Neutrophils also communicate with other immune cells, such as macrophages and lymphocytes, to coordinate the inflammatory response and activate the adaptive immunity. Neutrophils can secrete cytokines (signaling molecules) that can attract more immune cells to the site of infection or injury. They can also present antigens (molecules derived from pathogens) to lymphocytes to stimulate their activation and differentiation.

Neutrophils are short-lived cells that usually die after killing pathogens. They undergo a form of programmed cell death called apoptosis, which allows them to be cleared by macrophages without causing tissue damage. However, sometimes neutrophils can die by a process called necrosis, which releases their cytoplasmic contents into the surrounding tissue. This can cause inflammation and tissue damage, especially in chronic infections or autoimmune diseases.

Neutrophils are essential for fighting infections and healing injuries, but they can also cause harm if they are not regulated properly. Therefore, maintaining a normal neutrophil count and function is important for health and immunity.

To learn more about the fascinating mechanisms of neutrophils in action, you can watch this video lecture by Thomas Underhill, a professor of pathology and immunology at Washington University School of Medicine. In this lecture, he explains how neutrophils use different strategies to kill microbes, such as:

• Neutrophil extracellular traps (NETs): These are web-like structures composed of DNA and granule proteins that neutrophils release to trap and kill microbes. NETs can also modulate inflammation and immunity by interacting with other cells and molecules.
• Neutrophil swarms: These are clusters of neutrophils that form around a site of infection or injury. Neutrophil swarms enhance the recruitment and activation of more neutrophils, creating a positive feedback loop that amplifies the immune response.
• Neutrophil serine proteases (NSPs): These are enzymes that neutrophils store in their granules and secrete upon activation. NSPs can degrade various components of microbes, such as bacterial cell walls, toxins, and virulence factors. NSPs can also regulate inflammation and tissue repair by cleaving cytokines, chemokines, and extracellular matrix proteins.

The video lecture also covers some of the clinical implications of neutrophil mechanisms, such as how they contribute to chronic inflammatory diseases, autoimmune disorders, and cancer. You will also learn about some of the therapeutic approaches that target neutrophils or their products to treat these conditions.

The video lecture is about 50 minutes long and is suitable for anyone who wants to gain a deeper understanding of the role of neutrophils in health and disease.

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