The acquisition of granules and their content proteins is a critical part of the developmental program of the granulocyte. Arising at specific stages of neutrophil maturation, these intracellular and secretory organelles contain many of the requisite enzymes that mediate the oxidative and nonoxidative killing functions of the neutrophil (see Table 1).

Table1. Neutrophil Granules: Major Classes and Contents

Primary (azurophilic) granules are acquired at the promyelocyte stage and contain a wide array of proteins, including MPO, defensins, cathepsins, and NE. Secondary granules are secretory granules acquired at the transition to the myelocyte stage. Neutrophil secondary gran ules contain LF, the vitamin B12–binding protein transcobalamin I, the metalloproteinases (neutrophil collagenase and gelatinase), and NGAL. With the exception of gelatinase, which is also expressed by monocytes, expression of the secondary granule proteins is restricted within the hematopoietic lineage to neutrophils. Secondary granules and the synthesis of their contents therefore constitute a definitive marker of commitment to terminal neutrophil maturation. As dis cussed later, characteristic secondary granules are acquired at the same stage by eosinophils and basophils. Tertiary granules, containing primarily gelatinase, are formed during later stages of neutrophil maturation. Secretory vesicles are formed by endocytosis and contain plasma proteins.

On stimulation, the neutrophil first mobilizes secretory vesicles, which contribute their membrane proteins, including abundant integrin receptors, to the plasma membrane. This increases cellular adhesion by upregulating surface integrin expression in response to selectin stimulation or inflammatory mediators. Primary granules fuse with the phagosome and contribute to bacterial killing. Secondary and tertiary granules have multiple functions. Like primary granules, they fuse intracellularly with the phagosome to help promote bactericidal activity. They also contribute membrane proteins to the plasma membrane and are the source of the surface integrin receptor Mac-1 (CD11b/CD18) that is prominently upregulated during neutrophil activation. Secondary and tertiary granules also release the matrix modifying metalloproteinase collagenase (MMP8) and gelatinase (MMP9) into the extracellular milieu, enhancing neutrophil penetration into sites of inflammation. LF and transcobalamin I are thought to contribute to the antimicrobial response by sequestering iron and cobalamin, respectively, away from infecting organisms. LF has also been implicated in modulating neutrophil extracellular traps (NETs) by inhibiting their release.

The fusion of azurophilic and peroxidase-negative granules allows for cross-exposure of their contents within the phagosome. Under resting conditions, their constituent proteins are carefully sequestered in separate organelles, preventing premature activation and damage to the resting neutrophil. When granule fusion occurs, their protein contents cooperate to generate the antimicrobial response. Hydrogen peroxide, a by-product of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in secondary granules, combines with MPO from the primary granules to produce hypochlorous acid, a highly toxic microbicidal agent. The secondary granule proteins neutrophil gelatinase and neutrophil collagenase are produced as zymogens and are converted to their active forms by the action of NE released from the primary granules.

Current evidence largely supports the hypothesis that the con tent of the neutrophil granules is dictated primarily by the timing of synthesis of their respective content proteins. Multiple studies have demonstrated that each distinct granule population is generated not by differences in protein sorting but rather by a highly regulated transcriptional process that results in sequential gene expression. Expression of MPO occurs between the promyelocyte and the myelocyte stages of neutrophil development, and as a result it is packaged into the primary granules. Secondary granule proteins such as LF are expressed between the myelocyte and the metamyelocyte stages and hence are packaged into the secondary granules. Overexpression of the secondary granule protein NGAL in HL60 cells, a leukemic cell line that is arrested at the myeloblast stage of differentiation, results in its incorporation into primary granules, supporting the notion that gene expression and protein sorting into granules are coordinated events. However, this model may be an oversimplification because there is some overlap of expression between certain primary and secondary granule protein genes, and primary granule protein gene expression is much less synchronous than that of secondary granule proteins. The defensins are expressed later than other primary granule proteins, and defensin transcription appears to be regulated by the same transcriptional regulatory pathway as for the secondary gran ule proteins gelatinase and LF. The defensins are a family of small, variably cationic proteins that are highly abundant in the granules of mammalian phagocytes. Three defensins, HNP-1, -2, and -3, comprise 30% to 50% of total protein in the azurophilic granules of human neutrophils. Some defensins are broadly antimicrobial, antiviral, and cytotoxic, whereas others are chemotactic or opsonic or may modulate hormonal responses. The defensins are the only primary granule proteins that are absent in patients with neutrophil specific granule deficiency (SGD), which would predict targeting to the secondary granule. How defensins are packaged exclusively in the primary granule remains unclear.

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مواضيع ذات صلة

Transcription Factors Regulating Myeloid Differentiation and Myeloid-Specific Gene Expression

Cytokine Regulation of Myeloid Proliferation and Differentiation

Stages of Neutrophil Differentiation

T Lymphocytes, Transfer of Safety Genes, and Strategies to Improve Tumor Cell Specificity

Optimizing T-Cell Trafficking and Overcoming Tumor Immune Evasion

Allogeneic Banked Cells

Clinical Results of Chimeric Antigen Receptor T Cells in Hematologic Malignancies

Types of Cellular Immunotherapy

Adoptive Immunotherapy of Cancer

Therapeutic Manipulation of T-Cell-Mediated Immunity

T-Cell Exhaustion: Impaired Response after Chronic Antigen Exposure

T-Cell Memory