Neutrophils are white blood cells that are vital to the immune system. They help fight against infections and prevent inflammation. Keep reading to learn more about these cells.
What are Neutrophils?
Neutrophils are the most abundant immune cells in the body and play an important role in fighting against infections. They contain granules, which are storage structures that are important for antimicrobial effects [R].
Neutrophils, also called polymorphonuclear leukocytes (PMNs), develop in stem cells in the bone marrow. Chemokines (cytokines/signaling proteins) recruit neutrophils to the site of infection and inflammation [R].
However, neutrophils have a very short lifespan. They survive for less than 24 hours in the blood and will undergo self-destruction automatically [R].
The primary function of neutrophils is to prevent infection by attacking pathogens that try to invade the body [R].
Neutrophils pass through the bone marrow and blood vessels to the site of an injury (through transcellular migration) [R].
Their quick response makes them the first group of immune cells to participate in the body’s immune response. They produce antimicrobial substances and proteases (enzymes) that help degrade and kill pathogens [R].
After they finish defending the body against pathogens, some neutrophils activate macrophages (large white blood cells) to help with their removal. The limited lifespan of a neutrophil helps prevent further tissue injury and excess inflammation [R].
A normal neutrophil count differs by ethnicity. For healthy white adults, the normal count is 4.4 ×109/l (average range of 4.3 to 4.6 ×109/l). For healthy black adults, the normal count is 3.6 ×109/l (average range of 3.3 to 3.9 ×109/l) [R].
A stable neutrophil count can help protect against autoimmune diseases. High neutrophil levels may be a heart disease risk factor, while people with low levels are at risk for damage from invading organisms [R].
Negative Effects of High Neutrophil Levels
1) Can Worsen Cancer Prognosis
In general, neutrophils may play a role in the start of cancer, tumor formation, and the spreading of tumors to other places in the body (metastasis) [R].
Neutrophils contribute to inflammation by releasing reactive oxygen species. They also suppress the antitumor response (by stimulating TGFβ to release iNOS or ARG1 to suppress CD8+ T lymphocytes) [R].
The neutrophil to lymphocyte ratio (NLR) is a blood marker for various cancers (gut, lung, head, neck, ovarian, etc.). Multiple studies have shown that increased NLR is associated with poor prognosis in colon, pancreatic, stomach, and lung cancer [R, R, R, R].
In a review of over 100 studies and 40,000 patients, an NLR above 4 was associated with worse overall cancer survival rates [R].
2) Contributes to Heart Disease
Neutrophils enhance plaque inflammation in hardened arteries (atherosclerosis) [R].
After a heart attack, neutrophils clear the dead cells and debris around the injured area. After neutrophils die, macrophages release growth factors, causing inflammation and tissue formation, which make scars in the heart (cardiac fibrosis) [R].
A high neutrophil to lymphocyte ratio (NLR) is a predictor of heart disease. It is associated with an increased risk of irregular heartbeat (arrhythmia) and death in patients undergoing a procedure to treat heart disease (percutaneous coronary intervention) [R, R].
3) Contributes to Alzheimer’s Advancement
The hallmark of Alzheimer’s disease is brain inflammation. Neutrophils are found in swollen brain areas and may cause inflammation and blood-brain barrier damage. They recruit IL-17 cytokines, which are toxic to nerve cells [R].
Inhibiting neutrophil traffic to the brain may benefit Alzheimer’s patients. In a mouse model of Alzheimer’s, blocking neutrophil traffic to the brain prevented cognitive decline [R].
4) Contributes to Rheumatoid Arthritis
In arthritis patients, neutrophils in their joints damaged proteins and caused inflammation. In comparison to neutrophils from healthy patients, neutrophils from rheumatoid arthritis patients increased reactive oxygen species formation. All of these contribute to arthritis [R].
Neutrophils also release neutrophil extracellular traps (NETs), or antibodies that promote the immune response and inflammation. The more NETs circulating the body, the more severe the arthritis [R].
5) Negatively Affects Lung Injuries
Although neutrophils are highly important in immune defense activation in lung diseases, they can cause problems in the lungs as well. Increased activation of the cells can lead to tissue damage by releasing toxic agents (LL-37) [R].
Chest injuries can cause lung bruising (contusion), which may cause organ dysfunction and is possibly lethal. A review showed that during lung injuries, neutrophils increase CXCR2 production, which contributes to lung dysfunction [R].
Diseases Linked to High Neutrophil Levels
Abnormally high levels of neutrophils in the blood are called neutrophilia [R].
True neutrophilia is when the total blood count of neutrophils is increased in the body (above 9.5 ×109/l). It can occur from infections caused by bacteria, fungi, viruses, and parasitic infestations [R].
Neutrophilia can occur during diseases and infections, including pneumonia, meningitis, and cancer. It may be also hereditary and caused by a mutation in the CSF3R gene [R].
2) Neutrophilic Dermatoses
Neutrophilic dermatoses are a group of conditions where neutrophils accumulate in the skin, causing plaques, lesions, ulcers, and inflammation [R].
Like other autoimmune diseases, inflammatory cytokines (like IL-1B, IL-17, and TNF-a) play a role in the start of these diseases. A mutation in the PSTPIP1 can also play a role in neutrophilic dermatoses susceptibility [R].
Neutrophilic dermatoses diseases include [R]:
- Pyoderma gangrenosum
- Sweet’s syndrome
- Amicrobial pustulosis of the folds
Treatments for these conditions include immunosuppressants and glucocorticoids [R].
In a study of 41 major depressive disorder patients, their neutrophil and neutrophil/leukocyte ratios were higher when compared to healthy subjects. Neutrophil-induced inflammation may play a role in depression [R].
In a study of 456 acute appendicitis patients, the patients with an inflamed appendix had a significantly higher than normal neutrophil count. However, it does not indicate the severity of the illness and is not sensitive enough to be a disease marker [R].
On the other hand. a person’s neutrophil/lymphocyte ratio (NLR) can help predict appendicitis. According to a study of 240 children with appendicitis, an NLR above 3.5 can be a good indicator of appendicitis in both children and adults [R].
5) May Aggravate IBD
During a normal gut inflammatory response, neutrophils come to the inflammation site to help fight pathogens. However, during inflammatory bowel diseases (IBD), neutrophils may contribute to long-term inflammation and damage tissues [R].
Excessive neutrophil activity releases toxic products (TNF-a) and increased intestinal permeability (which lets more pathogens and microbes cross the intestines and harm the body). These contribute to IBD symptoms [R]
6) May Indicate Albuminuria
Albuminuria is when there is a high amount of albumin in urine. It is a sign of early kidney damage and blood vessel dysfunction. In a study (cross-sectional) of 2,265 elderly subjects, a high neutrophil count was associated with albuminuria [R].
A high neutrophil/lymphocyte ratio (NLR) can also predict albuminuria. In a 1.5-year pilot study of 112 diabetes patients, a high NLR was positively associated with albuminuria [R].
Diseases Linked to Low Neutrophil Counts
Abnormally low levels of neutrophils in the blood (lower than 1.5 ×109/l for longer than 6 months) is called neutropenia. Children may have temporary lower neutrophil levels due to viral infections, but this is not associated with any long-term health problems [R, R].
Neutropenia may be a result of a bone marrow disorder, where the bone marrow does not release enough neutrophils into the bloodstream. Infants can be born with neutropenia [R].
Other causes of neutropenia include [R]:
- Bacterial and viral infections
- Drugs and alcohol
2) Type 1 Diabetes
In a study of 410 type 1 diabetic patients and 700 healthy subjects, the diabetic patients had lower neutrophil levels, ranging from a 7 to 27% reduction. The patients that were at a greater risk for diabetes were the ones with the largest neutrophil reduction. However, after a few years, neutrophil levels returned to normal [R].
In a study of 30 obsessive-compulsive disorder (OCD) patients and 30 healthy controls, the patients had a lower average neutrophil count. Additionally, the OCD patients had lower TNF-a levels. Since neutrophils are a source of TNF-a, this is further evidence that lower neutrophil levels are associated with OCD [R].
In a study of 47 chronic fatigue syndrome (CFS) patients, their blood had lower levels of healthy neutrophils. They also had increased neutrophil cell death (apoptosis). Compared to healthy patients, they had more abnormalities in their immune cells [R].
Systemic lupus erythematosus (SLE), also known as lupus, is an autoimmune disease. Neutrophils may play a part in the start of lupus and the resulting organ damage from the disease. During lupus, neutrophils release neutrophil extracellular traps (NETs), or antibodies that can harm blood vessel cells and worsen organ damage R].
However, lupus patients have increased levels of neutrophil cell death (apoptosis). Many lupus patients also have neutropenia (abnormally low neutrophil levels). [R].
You can request that your doctor test your neutrophils. Conventional doctors will look at high or low neutrophil levels and not mention anything. Sometimes, a lab result may be in the reference range, but not actually be in the optimal range. Reference ranges are not the same as optimal ranges. This is why neutrophils even in the ‘normal’ range can be unhealthy and indicate that certain processes in the body aren’t optimal.
Ways to Increase or Decrease Neutrophil Count
Ways to Increase
Both folic acid (vitamin B9) and vitamin B12 deficiencies can cause neutrophil dysfunction. Eating foods rich in Vitamins B9 and B12, or taking supplements, can help improve neutrophil function and may increase their levels [R, R].
Ways to Decrease
People of African descent have lower neutrophil levels than those of European descent. This reduced count may be due to a variation in the Duffy Antigen Receptor for Chemokines (DARC) gene, called the “Duffy null polymorphism,” rs2814778 [R].
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 oddly shaped. However, patients with this disorder are mostly healthy and neutrophils still function normally. A mutation in the LBR gene causes Pelger-Huët anomaly [R].
Irregular Neutrophil Levels?
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