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Azurophilic granule
Azurophilic granule
Azurophilic granule
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Azurophilic granule
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Identifiers
LatinGranulum azurophilum
THH2.00.04.1.02011, H2.00.04.1.02014
Anatomical terms of microanatomy

An azurophilic granule is a cellular object readily stainable with a Romanowsky stain. In white blood cells and hyperchromatin, staining imparts a burgundy or merlot coloration. Neutrophils in particular are known for containing azurophils loaded with a wide variety of anti-microbial defensins that fuse with phagocytic vacuoles. Azurophils may contain myeloperoxidase, phospholipase A2, acid hydrolases, elastase, defensins, neutral serine proteases, bactericidal permeability-increasing protein,[1] lysozyme, cathepsin G, proteinase 3, and proteoglycans.[citation needed]

Azurophil granules are also known as "primary granules".[2]

Furthermore, the term "azurophils" may refer to a unique type of cells, identified only in reptiles. These cells are similar in size to so-called heterophils with abundant cytoplasm that is finely to coarsely granular and may sometimes contain vacuoles. Granules may impart a purplish hue to the cytoplasm, particularly to the outer region. Occasionally, azurophils are observed with vacuolated cytoplasm.[3]

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Azurophilic granule

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Azurophilic granules, also known as primary granules, are specialized lysosome-like organelles primarily found in , with similar granules also present in monocytes, the most abundant type of in , and are characterized by their dense, azurophilic (reddish-purple-staining) appearance under due to high concentrations of (MPO). The term 'azurophilic' refers to their affinity for azure dyes (oxidized forms of methylene blue), which impart a reddish-purple hue, a property first described by in the late when studying polymorphonuclear leukocytes. These granules serve as the primary storage compartment for potent antimicrobial and cytotoxic agents, enabling neutrophils to rapidly respond to infections by releasing these contents during or . Formed early in neutrophil maturation during the promyelocyte stage in the , their biogenesis is tightly regulated by transcription factors such as GATA-1, C/EBP-ε, AML-1, and c-Myc, ensuring the granules are packed with microbicidal proteins before the cell enters circulation. The contents of azurophilic granules include a diverse array of enzymes and peptides essential for destruction, such as MPO (which generates like ), serine proteases known as serprocidins (including neutrophil elastase, cathepsin G, proteinase 3, and azurocidin), α-defensins, and the bactericidal/permeability-increasing protein (BPI). These components work synergistically to disrupt microbial membranes, degrade bacterial proteins, and amplify oxidative killing within phagolysosomes or extracellularly. Membrane-associated proteins like and further facilitate granule docking and fusion with target membranes during activation. In terms of function, azurophilic granules are mobilized in response to strong stimuli, such as high intracellular calcium levels, following a hierarchical degranulation sequence where they are released last among granule types (after secretory vesicles, tertiary, and secondary granules) to minimize host tissue damage. This controlled release supports innate immunity by trapping and eliminating via mechanisms like (NETs), where granule proteins are externalized on DNA scaffolds. However, dysregulated can contribute to inflammatory diseases, including , (COPD), autoimmune conditions like , and viral infections such as , where granule-derived proteins such as proteinase 3 serve as autoantigens targeted by anti-neutrophil cytoplasmic antibodies (ANCAs). Additionally, the granules' glycoproteins exhibit unique paucimannose and phosphomannose glycans, which may modulate immune clearance and prevent excessive inflammation.

Overview

Definition

Azurophilic granules are peroxidase-positive primary granules that form during the early stages of granulopoiesis in promyelocytes. These organelles are characterized by their high content of myeloperoxidase (MPO), which accounts for approximately 5% of the neutrophil's dry weight and distinguishes them from other granule types through peroxidase cytochemistry. A defining feature of azurophilic granules is their affinity for Romanowsky-type stains, resulting from their rich endowment of basic (cationic) proteins, which impart a distinctive purple to burgundy coloration upon staining. This staining property, from which they derive their name, highlights their lysosomal-like nature and aids in their identification in cellular preparations. Azurophilic granules are primarily located in the of neutrophils, where they serve as storage compartments for components. They are synthesized exclusively during the immature stages of these cells—promyelocytes for neutrophils—and are not formed in mature circulating cells.

Historical Context

The discovery of azurophilic granules dates back to the early 20th century, when light microscopy of stained blood cells revealed distinct granular structures in developing leukocytes within . Researchers such as utilized vital techniques to study lineages in the , identifying granule-containing promyelocytes and early myeloid cells in mammalian , which laid foundational observations for understanding . These early studies highlighted the granules' prominence in immature neutrophils, distinguishing them from other cellular components through properties. The term "azurophilic" originated from the granules' affinity for azure dyes in Romanowsky-type stains, imparting a characteristic blue-purple (azure-like) hue, derived from the Greek word for blue. Developed in the late 19th century by Dmitri Romanowsky and refined in the early 1900s, these staining methods enabled visualization of the granules in promyelocytes and metamyelocytes, marking them as the first secretory organelles formed during neutrophil maturation. Initially termed "nonspecific" or "primitive" due to their uniform appearance across myeloid precursors, the granules were not fully differentiated from other vesicular structures in light microscopy observations. By the and , advancements in electron microscopy clarified their identity, revealing azurophilic granules as membrane-bound organelles rich in acid hydrolases, aligning them with Christian de Duve's concept of primary lysosomes. Seminal work by Dorothy F. Bainton and Marilyn G. demonstrated through cytochemical and ultrastructural analyses that these granules form exclusively in the promyelocyte stage and contain lysosomal enzymes like , dispelling earlier views of them as undifferentiated storage bodies. This recognition established azurophilic granules as specialized primary lysosomes essential to innate immunity, shifting their perception from mere staining artifacts to key cellular compartments.

Structure and Composition

Morphology

Azurophilic granules, also known as primary granules, in human neutrophils measure approximately 0.2 to 0.5 μm in diameter, with a mean size around 0.26 μm, making them larger than secondary granules. Under light microscopy, they appear as azurophilic (light blue-violet) structures due to their affinity for basic dyes, but their detailed morphology is best resolved via electron microscopy. Electron microscopy reveals azurophilic granules as spherical or organelles with an electron-dense core, often exhibiting a dense periphery surrounding a lighter interior. These granules form a heterogeneous population, with some displaying crystalline lattices, such as those composed of (MPO) crystals in elongated forms, while others appear amorphous without such ordered structures. This variability in internal architecture reflects differences in content density and maturation stages. The granules are enclosed by a single , which lacks lysosome-associated membrane proteins (LAMP-1 and LAMP-2), distinguishing them from typical lysosomes, but expresses mannose-6-phosphate receptors involved in targeting glycoproteins. This membrane composition supports their specialized role in function while influencing their electron-dense appearance under microscopy.

Molecular Components

Azurophilic granules, as primary lysosome-related organelles in neutrophils, are enriched with a diverse array of hydrolytic enzymes, , and other proteins that contribute to their microbicidal properties. These components are targeted to the granules via mannose-6-phosphate markers, which facilitate sorting from the trans-Golgi network, distinguishing them from conventional lysosomes that exhibit higher levels of LAMP-1 and LAMP-2 proteins. In contrast, azurophilic granules express LAMP-3 () on their membranes but maintain low LAMP-1/2 content, reflecting their specialized biogenesis. The major enzymes in azurophilic granules include (MPO), which constitutes approximately 5% of the 's dry weight and catalyzes the generation of for oxidative activity. , a , is another prominent component, alongside cathepsin G and proteinase 3, both of which belong to the chymotrypsin-like serprocidin family and exhibit broad proteolytic functions. Azurocidin (also known as cationic protein 37 or CAP37) further complements this enzymatic repertoire, contributing to the granules' digestive capacity. Antimicrobial peptides represent a significant fraction of the granule content, with α-defensins (human neutrophil peptides HNP1-4) accounting for about 5% of total neutrophil protein and forming pores in microbial membranes. The bactericidal/permeability-increasing protein (BPI) targets by binding , enhancing membrane disruption. Additional constituents include , which hydrolyzes bacterial peptidoglycans, and , a neutral localized primarily in the granule fraction that cleaves phospholipids to release precursors. Acid hydrolases, such as , provide general catabolic activity within the granules' acidic milieu, maintained by vacuolar-type H+-ATPase proton pumps.

Biogenesis

Developmental Formation

Azurophilic granules, also known as primary granules, begin forming during the promyelocyte stage of maturation in the . This process marks the commitment of precursor cells to the granulocytic lineage, distinguishing it from other hematopoietic pathways. The formation of these granules represents the first dedicated step in , where the cell shifts toward producing specialized antimicrobial structures. The of azurophilic granules occurs primarily during the promyelocyte stage, spanning approximately days 4 to 6 of overall development, preceding the formation of secondary or specific granules in subsequent stages. During this period, the promyelocyte nucleus remains large and round, and the fills with these electron-dense granules, which are visible under electron microscopy as membrane-bound organelles roughly 0.2–0.5 μm in . This timeline ensures that azurophilic granules are established before later maturation phases, providing the foundational lysosomal compartment for function. Synthesis ceases by the end of the promyelocyte stage, with the granules persisting through subsequent divisions but not increasing in number. Key enzymes destined for azurophilic granules, such as (MPO), are synthesized in the rough and trafficked through the Golgi apparatus. While some granule proteins bear mannose-6-phosphate (M6P) modifications, targeting to immature granules proceeds via alternative sorting mechanisms independent of M6P receptors, involving direct vesicular transport from the trans-Golgi network. This ensures selective delivery of lysosomal hydrolases and antimicrobial proteins. This mechanism is analogous to lysosomal targeting in other cell types but adapted for the regulated secretory pathway in neutrophils.

Biosynthetic Regulation

The biosynthesis of azurophilic granules is tightly regulated at the transcriptional level by key myeloid s that drive the expression of genes encoding granule proteins during early hematopoietic progenitor differentiation. C/EBPε, a myeloid-specific upregulated at the late myeloblastic and promyelocytic stages, induces the expression of critical azurophilic granule components such as (MPO), ensuring their timely production for primary granule formation. Similarly, PU.1, an ETS family transcription factor essential for myeloid lineage commitment, cooperates with other regulators like AML-1 and Sp3 to control the expression of azurophilic granule proteins, including bactericidal/permeability-increasing protein (BPI), thereby coordinating the genetic program for granule protein synthesis in early progenitors. These factors ensure that gene expression aligns with the developmental window for azurophilic granule assembly in promyelocytes. Post-transcriptional regulation involves specific sorting signals that direct lysosomal enzymes and other proteins to azurophilic granules. Post-transcriptional sorting involves specific signals directing proteins to azurophilic granules, with occurring in the granule lumen, as evidenced by the presence of M6P-containing proteins like MPO and cathepsin G within these organelles. This receptor-mediated sorting is crucial for lysosomal hydrolases, distinguishing azurophilic granules from conventional lysosomes despite shared enzymatic content. Additionally, many granule proteases, such as neutrophil and proteinase 3, are synthesized as inactive pro-forms in the ; upon arrival in the acidic environment of azurophilic granules, they undergo proteolytic by dipeptidyl peptidase I ( C) or other granule proteases, activating them for storage. Azurophilic granule heterogeneity arises from asynchronous synthesis of constituent proteins during promyelocyte maturation, resulting in subpopulations with varying protein ratios and densities. This temporal staggering in —where early-synthesized proteins like MPO accumulate first, followed by later ones such as —leads to distinct granule subsets, including low-density and high-density variants that differ in composition and trafficking . Such variability ensures functional diversity, with some subpopulations optimized for phagosomal fusion and others for controlled , reflecting the dynamic regulatory control over granule maturation.

Functions

Antimicrobial Activity

Azurophilic granules play a central role in the intracellular defense of neutrophils by fusing with phagosomes during , thereby delivering their contents to form phagolysosomes that facilitate destruction. This fusion process is selective and regulated, allowing the release of granule enzymes and proteins directly into the phagosomal compartment to target engulfed microbes without widespread cellular damage. Within the phagolysosome, azurophilic granule components mediate killing through both oxidative and non-oxidative mechanisms. Myeloperoxidase (MPO), a key enzyme stored in these granules, catalyzes the reaction of hydrogen peroxide (H₂O₂) and chloride ions to produce hypochlorous acid (HOCl), a potent oxidant that damages microbial proteins, lipids, and DNA, enabling rapid bacterial inactivation. Complementing this, non-oxidative pathways involve serine proteases like neutrophil elastase, which degrade bacterial cell walls and activate other antimicrobial factors, and cationic antimicrobial peptides such as defensins (e.g., human neutrophil peptides 1–4), which permeabilize microbial membranes by forming pores, leading to lysis of a broad spectrum of bacteria, fungi, and viruses. Beyond intracellular killing, azurophilic granules contribute to extracellular activity through (NETs) formed during NETosis, a process triggered by pathogens or inflammatory stimuli. In NETosis, nuclear DNA is decondensed and expelled, entwining with granule-derived proteins like MPO, , and to create web-like structures that ensnare and immobilize microbes, concentrating agents for efficient extracellular degradation without requiring . This mechanism provides broad-spectrum protection against invading pathogens in tissues where direct engulfment may be limited.

Inflammatory Roles

Azurophilic granules in neutrophils are primed for by inflammatory cytokines such as tumor factor-α (TNF-α), which enhances their fusion with the plasma membrane and subsequent release of contents during immune activation. This priming process involves signaling pathways like p38 MAPK and does not fully mobilize the granules on its own but significantly amplifies in response to secondary stimuli, such as pathogen-associated molecular patterns. In pro-inflammatory contexts, azurophilic granule-derived (NE) plays a key role by degrading components of the (ECM), such as and , which facilitates tissue infiltration and contributes to the amplification of inflammatory responses. This proteolytic activity promotes the recruitment of additional immune cells and can exacerbate tissue remodeling during acute inflammation. Conversely, bactericidal/permeability-increasing protein (BPI), another major component of these granules, exerts effects by neutralizing (LPS) from , thereby reducing excessive production (e.g., TNF-α and IL-6) and mitigating systemic inflammatory cascades. Azurophilic granules also contribute to inflammation resolution through the anti-inflammatory actions of their proteases, including NE, proteinase 3, and cathepsin G, which degrade excess inflammatory mediators such as and cytokines post-infection. This enzymatic degradation helps dampen prolonged immune activation, preventing excessive tissue damage and promoting the transition to tissue repair.

Comparison with Other Granules

Specific Granules

Specific granules, also known as secondary granules, form later in the maturation process of neutrophils, emerging at the and stages after the promyelocyte phase where azurophilic granules develop. These granules are peroxidase-negative, distinguishing them from the (MPO)-rich azurophilic granules that precede them in biogenesis. Their composition centers on antimicrobial and regulatory proteins such as , , and collagenase, which support iron sequestration, bacterial degradation, and remodeling, respectively. In contrast to azurophilic granules, specific granules lack MPO and serine proteases like and cathepsin G, resulting in a milder protein profile. Specific granules facilitate recruitment and mobility by releasing contents during and tissue traversal, enhancing and migration capabilities. They also contribute to early oxygen-dependent killing within phagosomes through fusion that delivers components supporting activity, though their antimicrobial effects are less potent and cytotoxic than those of azurophilic granules. Unlike azurophilic granules, which provide the primary intracellular killing machinery, specific granules emphasize extracellular and migratory functions.

Gelatinase Granules

Gelatinase granules, also known as tertiary granules, represent the final class of granules formed during maturation, emerging in the to stage within the . This late formation distinguishes them from earlier granule types, occurring as neutrophils approach full maturity over the final days of . Measuring approximately 0.1–0.2 µm in diameter, they are the smallest of the granule subsets, consisting of homotypically fused secretory vesicles derived from the trans-Golgi network. In terms of composition, gelatinase granules primarily contain matrix metalloproteinase-9 (MMP-9, or gelatinase B), which associates with gelatinase-associated lipocalin (NGAL), along with and vitamin B12-binding protein ( I). Their membrane incorporates receptors such as CD11b/CD18 and VAMP-2, facilitating rapid docking and fusion during . Notably, these granules lack the enzymes and cationic proteins found in azurophilic granules, such as and , emphasizing their non-toxic, remodeling-oriented role. Functionally, gelatinase granules support extravasation and tissue navigation by enabling diapedesis through endothelial barriers and basement membranes, where MMP-9 degrades components like . They also contribute to and inflammatory resolution via tissue remodeling activities, including arginase 1-mediated modulation. In the sequential hierarchy of neutrophil activation, gelatinase granules mobilize first in response to mild stimuli, preceding specific and azurophilic granules to prioritize migration over the potent antimicrobial release of the more toxic azurophilic subset.

Clinical Significance

Associated Disorders

Azurophilic granules play a critical role in neutrophil-mediated immune responses, and their dysfunction or aberrant activity is implicated in several disorders. (MPO) deficiency, an autosomal recessive condition, impairs the production of (HOCl) within these granules, leading to reduced capacity against certain pathogens. This deficiency results in increased susceptibility to fungal infections, particularly caused by Candida albicans, although most affected individuals remain . Severe cases exhibit recurrent severe infections due to defective killing of fungi by MPO-deficient neutrophils. Dysregulation of azurophilic granule is also central to autoinflammatory conditions driven by hyperactivity. Gain-of-function mutations in the gene, as seen in cryopyrin-associated periodic syndromes (CAPS) such as Muckle-Wells syndrome, promote excessive of azurophilic granules in neutrophils even under basal conditions. This leads to elevated release of azurophilic granule contents like MPO, contributing to and tissue damage characteristic of CAPS. Neutrophils from CAPS models show markedly increased granule secretion, linking activation directly to pathological . In autoimmune vasculitides, azurophilic granule proteins become autoantigens targeted by anti- cytoplasmic antibodies (ANCAs). Proteinase 3 (PR3), a stored in azurophilic granules, is a primary target of PR3-ANCAs, which are strongly associated with (GPA). These antibodies trigger activation, promoting granule and endothelial damage that drives small-vessel in GPA. The resulting release of PR3 and other granule components amplifies vascular and contributes to the necrotizing lesions observed in affected organs.

Diagnostic Applications

Azurophilic granules are visualized through light microscopy of peripheral blood smears stained with Wright-Giemsa, where their presence or absence aids in assessing maturation stages, particularly in leukemias. In normal maturation, these granules appear as coarse red-purple structures in promyelocytes and become less prominent in later stages like metamyelocytes and bands, reflecting the progression from primary to secondary granule formation. In acute myeloid leukemias (AML), such as AML M2 with maturation, blasts often exhibit delicate azurophilic granules or —fused azurophilic structures—helping distinguish myeloid lineage and maturation arrest from lymphoid leukemias. Myeloperoxidase (MPO), a hallmark stored in azurophilic granules, is detected via or histochemical to confirm myeloid lineage in blasts and identify MPO deficiency. using monoclonal anti-, after cell permeabilization, shows positivity in at least 3% of blasts for AML diagnosis, with high sensitivity (92%) in myeloid cases but potential false positives in some acute lymphoblastic leukemias depending on the antibody clone. Histochemical methods, such as cytochemical MPO , highlight activity in azurophilic granules of neutrophils and monocytes, enabling detection of congenital MPO deficiency, which affects up to 1 in 2,000-4,000 individuals and is characterized by absent or reduced in neutrophils. Antineutrophil cytoplasmic antibodies (ANCA) targeting azurophilic granule proteins, particularly MPO, are quantified using to diagnose ANCA-associated vasculitides. MPO-ANCA, reactive against MPO in azurophilic granules, is detected in 60-80% of cases and 18-60% of , with ELISA thresholds typically set at >5.0 IU/mL for positivity following initial . This serological testing supports early diagnosis of pauci-immune small-vessel vasculitides like and , where MPO-ANCA positivity correlates with renal and pulmonary involvement.

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