Neutrophils: Diagnostic Significance and Clinical Insights

Authors: Payal Bhandari M.D., Emilia Feria, Madison Granados 

 

Contributors: Vivi Chador, Hailey Chin




Neutrophils


Neutrophils are immune cells that attack harmful particles and pathogens by trapping and killing them. Produced by the spleen, they also aid in antibody production. Low neutrophil levels (neutropenia) suggest spleen dysfunction and higher infection risk, while high levels (leukocytosis) may indicate infection, inflammation, or cancer cell overgrowth.



Typical Adult Range


Ranges and thresholds can vary due to: 

(1) Lab-specific equipment, techniques, and chemicals, and 

(2) Patient demographics, including age, sex, and ethnicity.




Key Insights


Blood contains three types of cells:

  • Red blood cells (RBCs): Carry oxygen to tissues using hemoglobin, which gives blood its red color.

  • White blood cells (WBCs): Defend against infections, fight foreign invaders, and regulate inflammation and immune balance.

  • Platelets: Help stop bleeding by forming clots, repairing injuries, and supporting new blood vessel growth.

Figure 1: Blood consists of 55% plasma (mostly water with salts, proteins, lipids, and glucose), 45% red blood cells (RBCs), and 1% white blood cells (WBCs) and platelets. A thicker buffy coat indicates high WBC counts, as seen in leukemia, which means “whiteness of blood” in Greek. Unstained WBCs are colorless but are stained with hematoxylin and eosin to differentiate cell types, such as eosinophils, which absorb the pink eosin stain.


A WBC differential measures the five main types of white blood cells: neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Neutrophils, making up 55–70% of WBCs, are produced in the bone marrow at a rate of 100 billion daily. Neutrophil levels provide key insights into inflammatory conditions like infections, autoimmune disorders, vasculitis, blood cancer, and more. Lifestyle factors such as diet, medications, exercise, hydration, and stress can impact neutrophil counts and play a crucial role in managing related health conditions.



What Are Neutrophils?


Neutrophils are the first white blood cells (WBCs) to respond to inflammation, triggered by proteins like cytokines released by bacteria, viruses, or other invaders. Through chemotaxis, they follow cytokine trails, trap, and destroy invaders via phagocytosis. Neutrophils then recruit lymphocytes to produce antibodies for future defense, working together to prevent the spread and reproduction of foreign invaders.


Figure 2: Key functions of neutrophils in inflammation 4 (Neutrophils are vital in inflammation, responding to chemokine signals to locate injury sites. They roll along blood vessel walls, adhere to the endothelium, and exit the bloodstream through small openings. At the injury site, they bind to pathogens and release enzymes and reactive oxygen species (ROS) to destroy them. After completing their task, neutrophils undergo apoptosis, signaling macrophages to clear debris and resolve inflammation.



Let’s take viruses, for example. Viruses, much smaller than bacteria, are parasitic agents with RNA or DNA surrounded by a protein, fat, or sugar coat. They can only replicate inside host cells, like bacteria, and activate under stress, releasing toxins that damage cells and provide iron for replication.

Neutrophils respond quickly to eliminate viruses, but a weakened immune system allows viruses to spread through bodily fluids, direct contact, or contaminated food, water, and vectors like insects and animals6. 

                      

Figure 3: Viruses infect cells by attaching to specific receptors on the host cell surface. They inject genetic material or enter through endocytosis, taking over the cell to replicate and produce new viruses. These viruses are released to infect nearby cells, continuing the infection cycle 5 . 


Regulation of Neutrophil Formation and Elimination


All blood cells come from hematopoietic stem cells (HSCs), which differentiate into platelets, red blood cells (RBCs), and white blood cells (WBCs). WBCs develop into myeloid progenitor cells (CMPs) or lymphoid progenitor cells (CLPs). CMPs become eosinophils, basophils, monocytes, and neutrophils, while CLPs form T cells, B cells, and natural killer cells. Most WBCs (60–70%) are produced in bone marrow, with the rest made in the thymus, spleen, liver, and lymph nodes.

           

Figure 4: All blood cells originate from hematopoietic stem cells (hemocytoblasts), which differentiate into myeloid progenitor cells10. Bone marrow, mainly in flat bones like the skull, ribs, pelvis, and sternum, converts hemocytoblasts into red blood cells, platelets, and white blood cells, including monocytes, lymphocytes, eosinophils, neutrophils, and basophils.



Figure 5 shows how HSCs in bone marrow develop into neutrophils3 :  

  1. HSCs become multipotent progenitor (MPP) cells.

  2. MPPs transition to lymphoid-primed multipotent progenitors (LMPPs).

  3. LMPPs form granulocyte-monocyte progenitors (GMPs).

  4. GMPs develop into myeloblasts, promyelocytes, myelocytes, metamyelocytes, band cells, and mature neutrophils.

During maturation, neutrophils form segmented nuclei and granules with antimicrobial enzymes, earning them the name “segs” for their multilobed nuclei.



Figure 5: Neutrophils form in the bone marrow from hematopoietic stem cells (HSCs), which mature into myeloid progenitor cells and then neutrophil precursors. These develop through stages—myeloblast, promyelocyte, myelocyte, metamyelocyte, and band cell—gaining multi-lobed nuclei and enzyme-filled granules. Mature neutrophils enter the bloodstream to fight infections and inflammation. 



Neutrophils circulate in the blood for less than a day before being cleared by macrophages and dendritic cells in the lymphatic system, spleen, liver, and lymph nodes. The bone marrow constantly produces neutrophils to respond to pathogens, tissue injury, and inflammation. Their production is regulated by proteins like IL-23, IL-17, CXCR2, CXCR4, and G-CSF, influenced by microbes, circadian rhythms, and the nervous system. Old neutrophils signal their destruction by expressing CXCR4, reducing inflammation and neutrophil production3.

                        

Figure 6: After forming in the bone marrow, neutrophils enter the bloodstream as a key defense against infections. They are categorized into active and inactive pools. During inflammation or infection, neutrophils attach to blood vessel walls and migrate to tissues (chemotaxis) in response to signals from damaged tissues or pathogens, where they eliminate invaders 4 . 


Clinical Significance of a High Neutrophil Count (Neutrophilia)


Neutrophilia, a high neutrophil count (>7000 per microliter or >60% of WBCs),.is common in bacterial infections, oxidative stress, bone marrow disorders, and cancers. Dehydration, a key cause, reduces blood flow (vasoconstriction), affecting digestion, gut microbiota, and nutrient absorption. This leads to undigested food particles in the bloodstream, increasing blood viscosity, causing hypoxia, and overproducing reactive oxygen species (ROS). ROS damages cells, disrupts metabolism, and impairs cell function, fueling oxidative stress.

Figure 7: Healthy gut microbiota is essential for digestion, nutrient absorption, and waste excretion. Dysbiosis, or an imbalance in gut bacteria, disrupts metabolism and promotes harmful pathogens, affecting immune responses and overall health. 



Oxidative stress occurs when oxygen oxidizes LDL cholesterol, which deposits in injured blood vessels to form temporary plugs. White blood cells from the reticuloendothelial system clear cholesterol buildup, while platelets and smooth muscle form clots, scar tissue, and new blood vessels . This process, called oxidative stress-induced atherosclerosis, releases inflammatory proteins and reactive oxygen species (ROS) to recruit immune cells for tissue repair. 


Figure 8: Atherosclerosis thickens blood vessel walls with fat, scar tissue, and clots to repair injuries and prevent bleeding. It restricts blood flow, raises blood pressure, and redirects blood, causing backups in organs like the heart, liver, pancreas, and legs. This inflammation can damage organ structure and reduce function .



A 2017 study in the American Journal of Epidemiology linked rising neutrophil counts to worsening atherosclerosis and shorter lifespans 14 . Neutrophils work to contain pathogens like viruses, fungi, parasites, and bacteria, preventing them from releasing toxins that damage cells, mutate genes, and disrupt cell function5. Chronic inflammation can reduce blood flow, harm gut microbiota, and activate dormant viruses, which hijack host cells, deplete nutrients, and produce reactive oxygen species (ROS) that damage genetic material and cell function. 


Chronic atherosclerosis-induced inflammation and dysbiosis can overwhelm the reticuloendothelial system in the liver, spleen, intestines, and kidneys, reducing its ability to process toxins. Studies suggest one in ten cancers may result from this inflammation, which also contributes to chronic viral infections (e.g., HIV, HSV, EBV), blood clots, scar tissue, and organ damage.  

Figure 9: Chronic inflammation increases reactive oxygen species (ROS), proinflammatory proteins, and oxidized fats, activating white blood cells and platelets. This leads to tissue damage, clots, plaque buildup, and restricted blood flow.

          

Figure 10: Excess oxidized cholesterol, proinflammatory proteins, and reactive oxygen species damage tissues and weaken blood vessels. Tumor cells bind to cholesterol-laden arteries, activate platelets for clotting and angiogenesis, and evade natural killer (NK) cells. Inflammation promotes cancer growth and vessel invasion.


Clinical Significance of Low Neutrophil Count (Neutropenia)


Neutropenia, a low neutrophil count, affects 5–10%of people and compromises the immune system, which relies on the spleen, liver, lymph nodes, and bone marrow. Without neutrophils, infections and inflammation can quickly overwhelm the body. As of 2018, 1.24% of Americans (33.5 million) had neutropenia, with higher risk among Blacks, males, and young children . 

Autoimmune diseases affect 3–5% of the population and are rising. Type 1 diabetes (T1DM) affects 9.5% globally, with 8.4 million cases in 2021. Most diagnoses occur in adults aged 20–59, with a median onset age of 29. That year, 500,000 new cases were reported, and 35,000 undiagnosed individuals died within 12 months. Low-income countries account for 1.8 million T1DM cases, highlighting global disparities.


Type 2 Diabetes and Liver Diseases 

In 2015, 1 in 11 adults globally (415 million) had diabetes, with over 90% having type 2 diabetes (T2DM).14 Neutrophil activation is higher in obese T2DM patients, as shown by increased neutrophil elastase (NE) and myeloperoxidase (MPO) levels, which impair blood flow and gut microbiota function 14 . Dysbiosis leads to poor digestion, nutrient absorption, and waste removal, while rising neutrophils trigger inflammation, producing reactive oxygen species (ROS) and proinflammatory proteins that damage cells and disrupt metabolism. This chronic inflammation contributes to T2DM, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, and autoimmune disorders 14 . 


Over half of T2DM patients have NAFLD, which involves chronic inflammation, fibrosis, and liver cell death, often progressing to nonalcoholic steatohepatitis (NASH)33 14. Neutrophil infiltration worsens NASH severity, making NAFLD the leading cause of liver-related deaths globally. 14


Figure 11: The liver metabolizes cholesterol and proteins, produces amino acids and proteins, and detoxifies cellular waste. Liver dysfunction increases proinflammatory proteins and reactive oxygen species, causing chronic inflammation and overactivating neutrophils. This diverts nutrients and oxygen from other organs, impairing their function. Prolonged inflammation damages the liver, leading to conditions like steatohepatitis, fibrosis, and cirrhosis.


Type 1 Diabetes 

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease where reactive oxygen species (ROS) damage pancreatic cells, reducing insulin, glucagon, and leptin production. Insulin deficiency raises blood glucose and ROS levels, while the liver converts fats and proteins to fat storage, reducing fat metabolism14. Excess undigested proteins, fats, and glucose in the blood impair oxygen delivery (hypoxia), disrupting cell function and releasing toxic byproducts. Chronic inflammation overstimulates the reticuloendothelial system, leading to neutropenia . Research shows T1DM is marked by neutrophil infiltration into damaged organs, contributing to pancreatic beta-cell destruction14 . 


Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBD), including Crohn’s disease, ulcerative colitis (UC), celiac disease, and collagenous colitis, are autoimmune disorders affecting the digestive tract. UC impacts only the colon, while Crohn’s and other colitis can affect any part of the gut. Celiac disease, triggered by gluten, mainly affects the small intestine. IBD incidence is 10.9 per 100,000 annually, with a prevalence of 2.39 million people in the U.S., higher among Caucasians and those of Mexican descent.


IBD arises from environmental factors causing gut inflammation and dysbiosis 14 .  Stress activates the HPA axis and sympathetic nervous system, reducing gut blood flow and healthy bacteria, leading to overgrowth of harmful microbes like in small intestine bacterial overgrowth (SIBO). SIBO, common in IBD, involves neutrophils targeting undigested food particles to protect the gut lining. Chronic inflammation in IBD damages cells, disrupts organ function, and prevents normal physiological processes.


Chronic Obstructive Lung Diseases

In 2021, 14.2 million U.S. adults (6.5%) had chronic lung diseases like COPD, a figure unchanged since 2011. COPD is more common in rural areas due to higher smoking rates, aging populations, and socioeconomic challenges like poverty and limited healthcare access. Notably, 25% of COPD patients (3.8 million) have never smoked.


COPD involves increased neutrophil activity in the lungs, driven by hypoxia, which accelerates red blood cell damage and inflammation. Lung trauma disrupts oxygen delivery, triggering neutrophils to clear debris and heal tissues14. Megakaryocytes, typically found in bone marrow, migrate to the lungs during low oxygen levels, contributing to platelet production and linking COPD to vascular inflammation and autoimmune disorders 47.  


Figure 12: Low blood oxygen boosts red blood cell production, causing megakaryocytes (MKs) to leave the bone marrow and move to the lungs. When oxygen levels rise, MKs in the lungs form platelets, which are quickly destroyed. Chronic inflammation accelerates platelet breakdown, reducing liver thrombopoietin production and suppressing bone marrow platelet formation.

Conclusion

Neutrophil count is a key indicator of immune health and helps assess risks for various conditions. High neutrophil levels (neutrophilia) can increase inflammation, producing reactive oxygen species (ROS) that damage tissues, mutate genes, and disrupt cell function. Low neutrophil levels (neutropenia) are linked to chronic inflammation, raising the risk of vascular diseases, autoimmune disorders, infections, cancers, and organ dysfunction. Factors like poor nutrition, stress, and sleep issues can reduce blood flow, harm gut microbiota, impair digestion, and disrupt energy and hormone balance.

Managing abnormal neutrophil counts requires lifestyle changes, including a healthy diet, exercise, hydration, and stress management. Reducing medication use may also help restore balance, as drugs can complicate neutrophil production. A multidisciplinary approach can improve overall health, rebalance neutrophils, and lower the risk of serious health conditions.

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