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Granulocytes are a group of immune cells that are important in fighting pathogens and healing damaged cells. They play critical roles in inflammation and wound healing. High levels occur in infections, autoimmune diseases, and many cancers. Low levels are most often caused by infections and drugs. Read on to find out what high and low granulocyte levels mean and how you can decrease or increase your levels.
What Are Granulocytes?
Granulocytes are a type of white blood cell that contains small sacs called granules. The contents of these granules are released into the blood during infections, injuries, and allergic reactions. These contents include antimicrobial proteins, enzymes to digest bacteria, and reactive oxygen species [R].
There are four types of granulocytes [R]:
Granulocytes are made in the bone marrow from stem cells and then released into the circulation. They are part of the innate immune system, which provides a quick, general response to pathogens. Granulocytes become activated by pathogens and damaged cells [R].
Granulocytes are also known as polymorphonuclear leukocytes (PML) or polymorphonuclear neutrophils (PMN).
The main function of granulocytes is to engulf and destroy invading pathogens and parasites. They are responsible for starting the process of inflammation as well as resolving it. Granulocytes are also involved in wound healing and tissue remodeling [R, R].
Immune messenger molecules (eotaxin and IL-8) recruit granulocytes from the bloodstream to injured or infected tissues. They are then activated by bacteria, viruses, and fungi or damaged cells. When they encounter a pathogen, granulocytes engulf them. They then release the contents of their granules to digest and destroy them. However, they also can cause damage to your own cells in the process [R].
After a threat has been eliminated, granulocytes destroy themselves by programmed cell death (apoptosis). However, in many inflammatory diseases like rheumatoid arthritis and asthma, granulocytes last longer than they should [R].
Neutrophils are the most abundant granulocytes as well as the most abundant immune cells in the body. They make up 50% to 70% of all immune cells. They are very short-lived and only survive 8-12 hours in the blood (where they normally reside) and 1-2 days in tissues (when there is an infection) [R, R, R].
Neutrophils are among the first immune cells to arrive at the site of an injury or infection. They produce antimicrobial compounds called defensins, enzymes (proteases), and reactive oxygen species (superoxide and hydrogen peroxide) that break down and destroy pathogens. However, these compounds can also cause damage to the surrounding tissue. This can lead to delayed healing and excess scar tissue formation [R, R].
Eosinophils were thought to primarily fight multicellular parasites such as worms. However, recent research suggests that they may also allow some parasites to live while preventing them from doing too much damage. Together with mast cells and basophils, eosinophils play important roles in the development of allergy and asthma. They also play many other important roles including [R, R, R, R, R]:
- Fighting viral, bacterial, and fungal infections
- Activating acquired immunity (part of the immune system that develops a “memory” for pathogens)
- Helping prepare the uterus for pregnancy
- Repairing and remodeling tissue
- Regulating blood sugar and insulin levels
Like neutrophils, they are made in and mature in the bone marrow and then released into the bloodstream. However, unlike neutrophils, they are only in the blood for a short time (9-18 hours). Instead, they take up residence in the gut, ovaries, and lymph nodes, where they can live for several weeks. They are usually not found in the lung, skin, or throat except in disease states [R, R, R].
Basophils help fight bacteria, viruses, and parasites. They also play key roles in allergies and autoimmune diseases. They are the largest yet least common granulocyte in the body. Basophils reside in the bloodstream and are recruited to sites of inflammation when needed [R, R].
When basophils become activated, they release the contents of their granules, which includes heparin and histamine. Histamine expands blood vessels and increases blood flow. Heparin is an anti-clotting agent that helps maintain proper blood flow. This allows immune cells easy access to the site of inflammation [R, R, R].
Due to their similarity, mast cells were originally thought to be basophils. Whereas basophils mainly circulate in the bloodstream, mast cells live in most tissues throughout the body. They are especially abundant in places that come into close contact with the environment, such as the skin, the gut, and the airways [R, R, R].
Because of their location, mast cells are responsible for the early recognition of foreign invaders. Within seconds of encountering a pathogen, mast cells release histamine, enzymes, and heparin [R].
Mast cells can contribute to wound healing and the growth of new blood vessels (angiogenesis) [R].
Mast cells also play key roles in asthma and allergies by overreacting to the presence of harmless substances such as pollen and pet dander. They are the main contributors to the symptoms associated with these conditions. Mast cells also play roles in autoimmune conditions, including rheumatoid arthritis and multiple sclerosis [R].
By releasing pro-inflammatory cytokines (TNF-α and IL-6), mast cells can recruit T cells and dendritic cells to help fight pathogens. This makes mast cells a crucial link between the innate and adaptive immune systems [R].
Immature granulocytes are granulocytes that are still maturing. They are normally located in the bone marrow and have not yet matured into granulocytes [R, R].
Granulocytes Normal Range
Granulocytes are measured as part of a standard comprehensive blood count (CBC) test.
The normal range of granulocytes is 1.5-8.5 x 10^9/L or between 1,500 and 8,500 cells per microliter (mL) of blood.
Levels below this range are referred to as granulopenia. Granulopenia is commonly referred to as neutropenia (low neutrophil levels). Severely low levels (below 500 cells/µL) are referred to as agranulocytosis. Low levels of granulocytes reduce the body’s ability to fight infections [R].
Levels above this range are referred to as granulocytosis. Granulocytosis is commonly referred to as neutrophilia.
Causes of High Granulocytes
The sympathetic nervous system is responsible for the body’s fight-or-flight response. Granulocyte counts are normally elevated during pregnancy due to a higher sympathetic nervous system activity. This increased activity helps the developing fetus get enough oxygen and nutrients [R+].
2) Intense, Prolonged Exercise
Several studies of 141 total people have found that intense exercise including endurance exercise and strength training can substantially increase neutrophil levels. Exercise causes neutrophils to be released from the bone marrow at a higher rate [R, R, R, R, R, R, R, R].
Smoking was strongly linked to high granulocytes in a study of 38k people. In a study of 1,730 people, granulocytes levels decreased after smoking was stopped [R].
4) Sleep Loss
Sleep is incredibly important to the function of your immune system. In a pilot of study eight people, sleeping only four hours a night for three nights increased neutrophil levels by 34% [R].
Neutrophil levels increased by 30% after a single night of no sleep in 16 people (RCT) [R].
6) Heavy Metal and Chemical Poisoning
- Insect venom
7) Cushing’s Syndrome
Granulocyte levels increased in ten patients who underwent elective spine surgery due to an increase in cortisol [R]
Granulocyte levels were substantially higher in patients with appendicitis in a study of 456 people [R].
By increasing a protein called granulocyte colony stimulating factor (G-CSF), many cancers can cause the body to make too many granulocytes. Cancers that result in high granulocyte levels include [R, R, R, R, R]:
- Lymphoma (cancer of the lymphatic system)
- Chronic myeloid leukemia (cancer of the bone marrow)
11) Heart Attack
Neutrophils play an important role in repairing the damage done to the heart after a heart attack. Levels will greatly increase in the hours following a heart attack and are directly related to the degree of damage [R, R].
Diseases and Conditions Associated With High Granulocytes
1) High Blood Pressure
In a 40-year observational study of 9.4k people, high neutrophil levels increased the risk of developing high blood pressure [R].
Higher neutrophil levels were linked to fatigue due to stress from work in an observational study of 213 people [R].
3) Heart Disease (likely causal)
Neutrophils can accumulate in plaques in the artery walls and contribute to hardened arteries (atherosclerosis) [R].
High neutrophil and eosinophil levels are linked to an increased risk of heart disease. High neutrophils levels are also linked to increased risk for heart attack, stroke, and death from heart disease [R, R, R, R, R, R, R, R].
Ways to Decrease Granulocytes Levels
1) Vegan and Ketogenic Diets Decrease Granulocytes
2) Fasting Decreases Granulocytes
Ramadan is a religious practice in Islam that involves a month of intermittent fasts for most of the day (sunrise to sunset).
In a study of 28 Muslims, Ramadan decreased neutrophils by 18% [R].
Another study found Ramadan reduced neutrophils by 7% in 90 Muslims [R].
While fasting decreases neutrophils, it also improves their ability to engulf and destroy pathogens [R].
3) Getting Enough Sleep Prevents Increases in Granulocytes
4) Boswellia serrata Decreases Granulocytes
Boswellia serrata gum resin decreased eosinophils in a study 80 people (DB-RCT) [R]
5) Garlic (Allicin) Decreases Granulocytes
Neutrophil levels increased in rabbits infected with P. multocida bacteria. Allicin, the main active component of garlic, decreased neutrophil levels [R].
6) Reducing Stress May Prevent Increases in Granulocytes
Stress may increase neutrophil levels, which means that avoiding or managing stress may help prevent your neutrophil levels from increasing [R].
Causes of Low Granulocytes
1) Vitamin B9, Vitamin B12, and Iron Deficiencies
Iron deficiency can also lead to granulopenia. However, the mechanism for this is still unknown [R].
Certain bacterial, viral, protozoan and fungal infections can cause low granulocyte levels. The flu, Epstein-Barr virus (EBV), cytomegalovirus (CMV), and hepatitis A, B and C are common viruses that can lead to low granulocyte levels [R, R, R, R].
3) Autoimmune Disease
Systemic lupus erythematosus, also known as lupus, is an autoimmune disease. Neutrophils die at a much quicker rate in people with lupus. Because of this, low granulocyte levels are also seen in people with lupus, with 50% having abnormally low levels [R, R, R, R].
Low granulocyte levels are also a common feature of Sjögren’s syndrome, an autoimmune disease that causes dry eyes and mouth [R].
4) Bone Marrow Disorders
Bone marrow disorders can decrease granulocytes by interfering with their production. Examples of bone marrow disorders include [R]:
- Leukemia (bone marrow cancer)
- Aplastic anemia
6) Inborn Neutropenia
Congenital (inborn) neutropenia is a condition of low neutrophil levels from birth due to genetic disorders [R].
One example of congenital neutropenia is a condition called benign ethnic neutropenia (BEN). BEN is caused by a small genetic mutation. It is found in 25% to 50% of people of African descent and some ethnic groups in the Middle East. However, it is not associated with an increased risk of infection that is commonly seen in other forms of congenital neutropenia [R, R].
Other forms of congenital neutropenia include Kostmann’s syndrome and cyclic neutropenia [R].
7) Enlarged Spleen
8) Organ Transplants
Low neutrophil levels occur in up to 28% of kidney transplant and 24% of liver transplant recipients during the first year. Low neutrophil levels are associated with more infections and organ rejection in kidney transplant recipients, and bloodstream infections and increased risk of dying in liver transplant recipients [R].
9) Thyroid Disorders
Thyroid disorders (hypothyroidism and hyperthyroidism) are found in up to 43% of people with granulopenia. Both low and high thyroid hormones are thought to cause the destruction of granulocyte precursors. People with thyroid disorders also have high levels of antibodies to granulocytes, which causes the body to destroy them [R, R].
Hemodialysis is the use of a filter to clean the blood of people whose kidneys are not working properly. The process changes neutrophils so that they get stuck in the blood vessels, leading to low levels in the bloodstream [R, R].
11) Severe Burns
Diseases and Conditions Associated With Low Granulocytes
2) Type 1 Diabetes
Type 1 diabetes is an autoimmune disorder that causes the destruction of the cells that produce insulin (beta cells). Low neutrophil levels were associated with an increased risk of developing type 1 diabetes in a study of 436 people [R].
3) Obsessive-compulsive Disorder
Ways to Increase Granulocytes Levels
1) Intense Exercise Increases Granulocytes
2) Dark Chocolate Increases Granulocytes
3) Caffeine Increases Granulocytes
Caffeine increased both neutrophils and eosinophils in mice [R].
In a study (DB-RCT) of 22 people, caffeine increased neutrophil levels by 9%. In the group that exercised and supplemented with caffeine, neutrophil levels were increased by 58% [R].
Effects of Drugs on Granulocytes Levels
Drugs that increase granulocyte levels include:
Drugs that decrease granulocyte levels include:
- ACE inhibitors [R, R]
- Allopurinol [R]
- Pain-relieving drugs [R]
- Antibiotics [R]
- Anticoagulants [R]
- Antidepressants [R]
- Antidiabetics [R]
- Antiepileptics [R, R, R]
- Antihistamines [R]
- Antimalarial [R]
- Antipsychotics [R, R]
- Antithyroid medication [R, R, R]
- Chemotherapy [R, R]
- Cimetidine [R]
- Cocaine [R]
- Colchicine [R]
- Dapsone [R]
- Diuretics [R]
- Griseofulvin [R]
- Immunosuppressives [R]
- Levodopa [R]
- Levamisole [R]
- NSAIDs [R]
Genetics of Granulocytes
Gene Mutations and Neutropenia Risk
VPS45 is a gene that encodes a protein that helps control membrane trafficking. In a study of 7 children with mutations in the gene, the children had low neutrophil levels (neutropenia) and neutrophil dysfunction [R].
Mutations in the CXCR4 gene are associated with WHIM syndrome, a rare disease where the body’s immune system does not function properly. WHIM patients have severe low neutrophil levels (neutropenia) because neutrophils do not exit the bone marrow [R].
People with Kostmann’s disease have neutrophil levels lower than 0.2 ×109/l. Some of the patients have mutations in ELA2 or HAX-1. Additionally, Kostmann’s patients can also acquire CSF3R gene mutations [R].
Chediak-Higashi patients have CHS1 gene mutations, which can cause neutropenia [R].
Shwachman-Diamond is a rare disorder, where the patients have defective neutrophil movement in the blood. The SBDS gene has a mutation that is associated with neutropenia [R].
Gene Mutations and Neutrophilia Risk
A mutation in the CSF3R gene promotes neutrophil formation. This can lead to higher susceptibility for hereditary chronic neutrophilia [R].
PSTPIP1 mutation can play a role in neutrophilic dermatoses susceptibility [R].
People with the GPSM3 SNP rs204989 may have decreased GPSM3 production and be protected against rheumatoid arthritis. This specific variation reduces neutrophil movement to the inflammation site, which prevents long-term inflammation that is associated with arthritis [R].
A mutation in the RAC2 gene is associated with neutrophil dysfunction and can cause a person to be predisposed to bacterial infections. It is also associated with human immunodeficiency syndrome [R].
Pelger-Huët anomaly is a genetic disorder where the nucleus of neutrophils is in odd shapes. However, patients with this disorder are mostly healthy and neutrophils still function normally. A mutation in the LBR gene causes Pelger-Huët anomaly [R].
Eosinophils and Basophils
Abnormal Granulocyte Levels?
People go to their doctor to get their granulocyte levels tested as part of a complete blood count (CBC) test. Almost always, the results are not scrutinized, even though we know that you can be healthier and live longer when your results lie within optimal ranges. When I used to go to doctors and tried to discuss my results, they had no clue what these meant from a health perspective. All they cared about was whether they could diagnose me with some disease. This is why we created Lab Test Analyzer, a tool that easily lets you know which lab results you need to be concerned about, and how to bring these within the optimal range.
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