Neutrophils: Neutrophil Function, Origin and Related Conditions

Our understanding of the immune system is continually evolving; what we previously understood develops on a regular basis as more experiments are performed and the complexity inherent within it grows with each passing year. One very good example of this is our knowledge of neutrophils, once seen simply as cells that devoured invading pathogens, we now understand to orchestrate far more than this apparently simple task.

In this article, we consider what neutrophils are, how they are generated, their function in the body and medical conditions related to them.

What are neutrophils?

Neutrophils, also known as polymorphonuclear (PMN) leukocytes, like basophils and eosinophils, are part of the granulocyte group of immune cells. They were first described and named due to their neutral staining properties by Paul Ehrlich in 1879¹ for which he was awarded the Nobel prize, along with Élie Metchnikoff, in 1908.² They are classically viewed as effector cells as part of the innate immune system, playing an important role in the prevention of bacterial, fungal and some viral infections. However, more recent research has shown that they play a critical role in regulating both the innate and adaptive immune responses.

They are the most abundant white blood cell and comprise 50–70% of the population under normal conditions.³ Neutrophils have multi-lobed nuclei generally with 3–5 segments joined by thin strands, hence the name PMN, are spherical and 12–15 µm in diameter. ⁴ They contain at least four types of granule in the cytoplasm as shown in Table 1.

Table 1: A table showing the different type of neutrophil granule and their contents. ^5,6:

Neutrophil development, like that of eosinophils and basophils, occurs in the bone marrow. They begin life as multipotent hematopoietic stem cells with the ability to differentiate into multiple different cell types. As with other granulocytes, the stem cells must differentiate into a myeloid progenitor cell or myeloblast [Updated, May 13, 2024] with the shared properties of both types of cell, followed by a granulocyte–macrophage progenitor, granulocyte progenitor and then further on into the specific neutrophil lineage (Figure 1).⁷ Once mature, the neutrophils leave the bone marrow and enter the circulatory system where they migrate to sites of infection and inflammation. The development and release of neutrophils into the circulation is a very complex process that is regulated by a number of different factors including:

1. Cytokines, e.g., interleukin-3, granulocyte–macrophage colony-stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF)
2. Transcription factors, e.g., CCAAT/enhancer-binding protein (C/EBP) family members and GATA binding proteins
3. Chemokines and chemokine receptors, e.g., stromal cell-derived factor 1, interleukin-8, CXCR4 and CXCR2
4. Bone marrow stromal cells

Although classically thought of as a fairly homogeneous population of cells, more recent research has shown that there are a variety of neutrophil subsets that exhibit differences in phenotype, tissue localization and function, including classical neutrophils, tumor associated neutrophils (TANs), immature neutrophils (band cells) and low-density neutrophils (LDNs). ⁸

Figure 1: Diagram showing the differentiation pathway for the development of neutrophils. Credit: Technology Networks.

Neutrophil function

Neutrophil migration to the site of infection is dependent on both pathogen-derived chemicals and inflammatory mediators like C5a, C3a, leukotriene lipids, chemokines and formyl peptides.⁹ Once there, they are capable of dealing with agents in a variety of ways (Figure 2):

1. Engulf pathogens (phagocytosis) and then release the contents of azurophilic and specific granules into the phagosome to kill the invading agent.
2. Release the contents of specific granules, gelatinase granules and secretory vesicles via the process of degranulation and exocytosis into the extracellular space to kill the invading pathogen.
3. Produce reactive oxygen species (ROS) like hydrogen peroxide (H₂O₂) both internally and externally that damage pathogens.
4. Undergo the process of NETosis by releasing extracellular traps (NETs), which are web-like structures composed of DNA, histones and antimicrobial proteins that trap and kill pathogens.
5. Modulate inflammation and both the innate and adaptive immune responses using a variety of mechanisms including release of alarmins, cytokines and NETs, and antigen presentation to CD4 T cells. They have also been shown to interact with a wide variety of both immune and nonimmune cells such as platelets, mesenchymal stem cells, mast cells, monocytes, macrophages, dendritic cells (DCs) and innate lymphoid cells, B cells and T cells.^10,11

Figure 2: Neutrophil functions. Credit: Technology Networks.

In addition to the functions described above, neutrophils have been shown to be essential in the progression of some cancers by promoting angiogenesis, immunosuppression and metastasis.¹²

What are absolute neutrophils?

Absolute neutrophils or absolute neutrophil count (ANC) refers to the actual number of neutrophils circulating in the blood, normally measured per microliter (μL) of blood, with the typical range being 2500–7000. It is an important parameter in assessing an individual’s immune status, particularly their ability to fight off infections. The ANC is calculated by multiplying the total white blood cell count by the percentage of neutrophils (expressed as a decimal fraction).¹³

Continue reading below...

Looking for content on The Immune System?

Visit this Topic Page to find a variety of curated content on The Immune System.

Visit Topic Page

Neutrophil-related conditions

Neutrophils are involved in a wide range of physiological and pathological conditions. Changes in neutrophil counts, either depleted (neutropenia)¹⁴ or elevated (neutrophilia),¹⁵ or function can be indicative of various health issues, some of which are described below.

1. Autoimmune disorders: Neutrophils can be involved in the pathogenesis of autoimmune conditions such as systemic lupus erythematosus (SLE)¹⁶ and vasculitis. The etiology of SLE is not well characterized, but it affects mainly women of childbearing age and recent evidence suggests that neutrophils are involved in the initiation, perpetuation and damage associated with the condition.
2. Infections: Neutrophils are crucial for the body's defense against bacterial, fungal and certain viral infections. Neutrophilia can occur in response to acute bacterial infections, particularly pyogenic infections with bacteria like streptococci and staphycococci.¹⁷ Neutropenia can result from severe infections including salmonella, mycobacteria, HIV, EBV and hepatitis.¹⁸
3. Trauma and tissue injury: Neutrophils are among the first responders to tissue injury, where they help clear debris and fight potential infections. In conditions such as burns¹⁹ and trauma,²⁰ neutrophils can contribute to tissue damage if their response is dysregulated.
4. Inflammatory disorders: A variety of conditions characterized by chronic inflammation, such as atherosclerosis, asthma, rheumatoid arthritis and inflammatory bowel disease (e.g., Crohn's disease), can be associated with abnormal neutrophil activity and migration into affected tissues.²¹
5. Leukemias and myeloproliferative disorders: Neutrophil abnormalities can occur in various types of leukemia and myeloproliferative neoplasms, characterized by abnormal proliferation of myeloid cells in the bone marrow. For example, chronic neutrophilic leukemia (CNL), which has been associated with CSF3R mutations.²²
6. Medication side effects: Certain medications, such as chemotherapy drugs, some antibiotics (e.g., vancomycin and penicillin G) and clozapine can cause neutropenia by suppressing bone marrow function and leading to increased susceptibility to disease.²³
7. Bone marrow disorders: Conditions affecting the bone marrow, such as aplastic anemia,²⁴ myelodysplastic syndromes (MDS)²⁵ and congenital neutropenia,²⁶ can lead to neutropenia and result in an increased susceptibility to infections.

Historically, neutrophils were considered to be a fairly homogeneous population of cells of the innate immune system, seen as the first line of defense acting to prevent infection from invading microbial pathogens. However, recent research has shed light on their heterogeneity and involvement in the body’s whole immune and inflammatory responses.

Correction: A typographical error in this article erroneously stated that myoblasts were another name for proliferating myeloid progenitor cells, this was updated on May 13, 2024, to correctly identify myeloblasts as the alternative terminology.