Are Neutrophils Myeloid Cells? Insights on Their Lineage

Neutrophils are a crucial component of the immune system, playing a frontline role in defending against infections. As the most abundant white blood cells, they respond rapidly to invading pathogens. Their ability to engulf microbes, release antimicrobial substances, and coordinate with other immune cells makes them essential for maintaining health.

Classification In The Myeloid Lineage

Neutrophils belong to the myeloid lineage, distinguishing them from lymphoid-derived immune cells. They originate from hematopoietic stem cells (HSCs) in the bone marrow, which differentiate into myeloid progenitors before giving rise to granulocytes, monocytes, erythrocytes, and megakaryocytes. As granulocytes, neutrophils contain cytoplasmic granules filled with enzymes and antimicrobial proteins.

Their differentiation from common myeloid progenitors (CMPs) follows a well-defined trajectory. CMPs give rise to granulocyte-monocyte progenitors (GMPs), which further specialize into neutrophil precursors. This process is regulated by transcription factors such as CCAAT/enhancer-binding protein alpha (C/EBPα) and PU.1, which drive gene expression necessary for maturation. These regulatory elements align neutrophils with macrophages and dendritic cells, which also originate from GMPs but diverge later in development.

Neutrophils share structural and biochemical traits with other myeloid cells. Their granules, containing myeloperoxidase, neutrophil elastase, and cathepsins, function similarly to the lysosomes in monocytes and macrophages. Additionally, neutrophils express surface markers such as CD11b and CD15, commonly found on other myeloid-derived cells, highlighting evolutionary conservation in immune function.

Origin In Bone Marrow

Neutrophils develop in the bone marrow through a tightly regulated hematopoietic process. Hematopoietic stem cells (HSCs) in specialized bone marrow niches differentiate into CMPs, which serve as precursors for multiple blood cell types. The transition from CMPs to neutrophils is shaped by transcription factors, cytokines, and cellular interactions.

A key stage in neutrophil development occurs when CMPs differentiate into GMPs, committing to the granulocytic lineage. C/EBPα plays a crucial role in initiating gene expression for neutrophil maturation. This transcriptional program leads to the formation of myeloblasts, the earliest identifiable neutrophil precursors. Myeloblasts progress through promyelocytes, myelocytes, and metamyelocytes before reaching the band cell stage, the final step before full maturation. Each stage is marked by distinct morphological changes, including the accumulation of cytoplasmic granules filled with antimicrobial enzymes.

The bone marrow microenvironment orchestrates neutrophil production by providing essential signaling molecules. Granulocyte colony-stimulating factor (G-CSF) binds to receptors on neutrophil precursors, promoting survival, expansion, and functional maturation. During infections or inflammation, increased G-CSF levels accelerate neutrophil production. Bone marrow stromal cells, including mesenchymal stem cells and endothelial cells, further regulate neutrophil retention and release through cytokine secretion and adhesion molecule presentation.

Structural And Functional Features

Neutrophils have a distinct structure that supports their physiological roles. Their nucleus, segmented into multiple lobes, enhances flexibility, allowing them to navigate through narrow capillaries and dense tissues. This lobulated structure facilitates rapid movement through endothelial barriers. Their cytoplasm contains granules categorized as primary (azurophilic), secondary (specific), and tertiary, each storing specialized enzymes and antimicrobial proteins. These granules release their contents in response to external stimuli, ensuring a rapid biochemical response.

Azurophilic granules, which develop early in neutrophil maturation, contain potent enzymes such as myeloperoxidase and cathepsins for intracellular processing. Specific granules store proteins like lactoferrin and lysozyme, which modulate extracellular conditions. Tertiary granules, enriched with metalloproteinases, assist in tissue remodeling and migration. The sequential release of these granules follows a regulated order aligned with neutrophil activation states, fine-tuning interactions with surrounding cells while preventing unnecessary tissue damage.

Neutrophils also possess surface receptors that govern their ability to perceive and react to environmental signals. Integrins, selectins, and pattern recognition molecules mediate adhesion, migration, and biochemical signaling. Integrins such as CD11b/CD18 facilitate interactions with endothelial cells, enabling firm adhesion before transmigration into tissues. Selectins support initial tethering and rolling along blood vessel walls. Pattern recognition receptors, including Toll-like receptors (TLRs), detect molecular patterns associated with cellular stress, integrating multiple signaling pathways for a rapid yet controlled response.

Variation In Neutrophil Subpopulations

Neutrophils were traditionally viewed as a uniform population of short-lived cells, but emerging research reveals significant heterogeneity. Variations in phenotype, gene expression, and functional properties define distinct neutrophil subpopulations that adapt to different physiological and pathological conditions. These subpopulations differ in surface markers, activation states, and lifespan, leading to specialized roles beyond pathogen clearance. Advances in single-cell RNA sequencing and flow cytometry have identified subsets with distinct inflammatory potential, tissue residency, and immunoregulatory functions.

One well-characterized subset, low-density neutrophils (LDNs), appears in pathological states such as cancer and autoimmune diseases. LDNs display altered morphology and gene expression patterns, often exhibiting enhanced pro-inflammatory activity or immunosuppressive functions depending on the disease context. Their presence in peripheral blood and association with disease progression highlight their clinical significance. Another subset, aged neutrophils, arises as these cells circulate longer in the bloodstream. Characterized by increased expression of CD62L and CXCR4, aged neutrophils are primed for clearance by the bone marrow, maintaining homeostatic balance and preventing excessive immune activation.

Comparisons With Other Myeloid Cells

Although neutrophils share their myeloid lineage with monocytes, macrophages, and dendritic cells, they exhibit distinct characteristics. Neutrophils respond rapidly to infections but have a short lifespan, typically surviving only 6 to 12 hours in circulation before undergoing apoptosis. In contrast, monocytes persist for days before differentiating into macrophages or dendritic cells, which contribute to prolonged immune modulation and tissue repair.

Neutrophils specialize in acute inflammation, relying on their granules and oxidative burst to neutralize pathogens quickly. Macrophages, in contrast, play a more versatile role, engulfing microbes, presenting antigens to T cells, and secreting cytokines that shape immune responses. Dendritic cells primarily function in antigen presentation, bridging innate and adaptive immunity. Despite these differences, neutrophils and other myeloid cells share overlapping signaling pathways, such as those mediated by Toll-like receptors (TLRs) and cytokine receptors, ensuring coordinated immune responses.

Role In Pathophysiological Conditions

Beyond their role in host defense, neutrophils contribute to various pathological conditions, where their excessive activation or dysfunction can drive disease progression. Their involvement extends beyond infections to chronic inflammatory disorders, autoimmune diseases, and cancer, where they can either exacerbate pathology or contribute to immune regulation.

In inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease, neutrophils release excessive reactive oxygen species and proteolytic enzymes, damaging tissues and perpetuating chronic inflammation. In cancer, their role is complex—tumor-associated neutrophils (TANs) can either promote tumor growth through angiogenesis and immunosuppression or enhance anti-tumor immunity by recruiting cytotoxic immune cells. This dual nature underscores the need for further research into neutrophil-targeted therapies that modulate their function in disease contexts.