Neutrophils are the most abundant leukocytes (white blood cells), indispensable in defending the body against invading microorganisms. In response to infection, neutrophils leave the circulation and migrate towards the inflammatory focus. They contain several subsets of granules that are mobilized to fuse with the cell membrane or phagosomal membrane, resulting in the exocytosis or exposure of membrane proteins. Traditionally, neutrophil granule constituents are described as antimicrobial or proteolytic, but granules also introduce membrane proteins to the cell surface, changing how the neutrophil responds to its environment (Borregaard et al. 2007). Primed neutrophils actively secrete cytokines and other inflammatory mediators and can present antigens via MHC II, stimulating T-cells (Wright et al. 2010).
Granules form during neutrophil differentiation. Granule subtypes can be distinguished by their content but overlap in structure and composition. The differences are believed to be a consequence of changing protein expression and differential timing of granule formation during the terminal processes of neutrophil differentiation, rather than sorting (Le Cabec et al. 1996).
The classical granule subsets are Azurophil or primary granules (AG), secondary granules (SG) and gelatinase granules (GG). Neutrophils also contain exocytosable storage cell organelles, storage vesicles (SV), formed by endocytosis they contain many cell-surface markers and extracellular, plasma proteins (Borregaard et al. 1992). Ficolin-1-rich granules (FG) are like GGs highly exocytosable but gelatinase-poor (Rorvig et al. 2009).
View original pathway at Reactome.
Pepys MB, Hawkins PN, Booth DR, Vigushin DM, Tennent GA, Soutar AK, Totty N, Nguyen O, Blake CC, Terry CJ.; ''Human lysozyme gene mutations cause hereditary systemic amyloidosis.''; PubMedEurope PMCScholia
Chen YT, He JK, Ding JH, Brown BI.; ''Glycogen debranching enzyme: purification, antibody characterization, and immunoblot analyses of type III glycogen storage disease.''; PubMedEurope PMCScholia
Campbell EJ, Silverman EK, Campbell MA.; ''Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity.''; PubMedEurope PMCScholia
Rørvig S, Østergaard O, Heegaard NH, Borregaard N.; ''Proteome profiling of human neutrophil granule subsets, secretory vesicles, and cell membrane: correlation with transcriptome profiling of neutrophil precursors.''; PubMedEurope PMCScholia
Kitamura T, Naganuma T, Abe K, Nakahara K, Ohno Y, Kihara A.; ''Substrate specificity, plasma membrane localization, and lipid modification of the aldehyde dehydrogenase ALDH3B1.''; PubMedEurope PMCScholia
Putnam CD, Arvai AS, Bourne Y, Tainer JA.; ''Active and inhibited human catalase structures: ligand and NADPH binding and catalytic mechanism.''; PubMedEurope PMCScholia
Le Cabec V, Cowland JB, Calafat J, Borregaard N.; ''Targeting of proteins to granule subsets is determined by timing and not by sorting: The specific granule protein NGAL is localized to azurophil granules when expressed in HL-60 cells.''; PubMedEurope PMCScholia
Barbetti F, Rocchi M, Bossolasco M, Cordera R, Sbraccia P, Finelli P, Consalez GG.; ''The human skeletal muscle glycogenin gene: cDNA, tissue expression and chromosomal localization.''; PubMedEurope PMCScholia
Pessin JE, Bell GI.; ''Mammalian facilitative glucose transporter family: structure and molecular regulation.''; PubMedEurope PMCScholia
Borregaard N, Sørensen OE, Theilgaard-Mönch K.; ''Neutrophil granules: a library of innate immunity proteins.''; PubMedEurope PMCScholia
Wright HL, Moots RJ, Bucknall RC, Edwards SW.; ''Neutrophil function in inflammation and inflammatory diseases.''; PubMedEurope PMCScholia
Kanyo ZF, Scolnick LR, Ash DE, Christianson DW.; ''Structure of a unique binuclear manganese cluster in arginase.''; PubMedEurope PMCScholia
Shen J, Bao Y, Liu HM, Lee P, Leonard JV, Chen YT.; ''Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle.''; PubMedEurope PMCScholia
Gibbons BJ, Roach PJ, Hurley TD.; ''Crystal structure of the autocatalytic initiator of glycogen biosynthesis, glycogenin.''; PubMedEurope PMCScholia
Tao N, Wagner SJ, Lublin DM.; ''CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails.''; PubMedEurope PMCScholia
Borregaard N, Kjeldsen L, Rygaard K, Bastholm L, Nielsen MH, Sengeløv H, Bjerrum OW, Johnsen AH.; ''Stimulus-dependent secretion of plasma proteins from human neutrophils.''; PubMedEurope PMCScholia
Rab3A, located in the synaptic vesicle membrane, interacts with RIM ( Rab3A interacting Molecule) and with Doc2. These interactions are beleived to initiate the process of priming which precedes the fuison of the synaptic vesicle with the plasma membrane.
Azurophil or primary granules were originally defined by their high content of myeloperoxidase (MPO) and their affinity for the basic dye azure A (Spicer & Hardin 1969). Azurophil granules are generally described as spherical. Like lysosomes, they contain CD63 in their membrane (Cham et al. 1994) but are regarded as specialized secretory granules rather than lysosomes (Cieutat et al. 1998). Azurophil granules undergo limited exocytosis in response to stimulation (Sengelov et al. 1993, Faurschou et al. 2002), their primary role is believed to be killing and degradation of engulfed microbes in the phagolysosome (Joiner et al. 1989).
Secretory vesicles provide a reservoir of membrane-associated receptors that are required at the earliest stages of the neutrophil-mediated inflammatory response. They are mobilized in response to a wide variety of inflammatory stimuli (Sengelov et al. 1993a,b). Resultant cell surface changes allow the neutrophil to establish firm contact with activated vascular epithelium (Faurschou & Borregaard 2003).
Tertiary (gelatinase) granules are part of a continuum of peroxidase-negative granules formed in myelocytes, metamyelocytes, band cells and segmented neutrophils. They differ from secondary granules by having a low content of antimicrobial substances, and are more readily exocytosed (Sengelov et al. 1995). Tertiary granules are primarily a reservoir of extracellular matrix degrading enzymes and membrane receptors that are needed for neutrophil extravasation and diapedesis (Faurschou & Borregaard 2003).
Tertiary (gelatinase) granules are part of a continuum of peroxidase-negative granules formed in myelocytes, metamyelocytes, band cells and segmented neutrophils. They differ from secondary granules by having a low content of antimicrobial substances, and are more readily exocytosed (Sengelov et al. 1995). Tertiary granules are primarily a reservoir of extracellular matrix degrading enzymes and membrane receptors that are required for neutrophil extravasation and diapedesis (Faurschou & Borregaard 2003).
Secretory vesicles provide a reservoir of secreted proteins and membrane-associated receptors that are required at the earliest stages of the neutrophil-mediated inflammatory response. They are mobilized in response to a wide variety of inflammatory stimuli (Sengelov et al. 1993a,b). Resultant cell surface changes allow the neutrophil to establish firm contact with activated vascular epithelium (Faurschou & Borregaard 2003).
Secondary (specific) granules are peroxidase-negative and rich in antimicrobial substances (Joiner et al. 1989, Rorvig et al. 2012). They are more irregular and elongated in form than azurophil granules (Bainton et al. 1971). This might reflect volume adjustment in azurophil granules, which are known to proteolytically process a significant fraction of the proteins that are targeted to them, while little or no processing and therefore no increase in osmotic activity due to proteolysis has been observed in secondary granules (Borregaard & Cowland 1997). Secondary and tertiary granules have overlapping contents but can be discriminated by their intrinsic buoyant densities when centrifuged on gradient media (Kjeldsen et al. 1994).
Azurophil or primary granules were originally defined by their high content of myeloperoxidase (MPO) and their affinity for the basic dye azure A (Spicer & Hardin 1969). Azurophil granules are generally described as spherical. Like lysosomes, they contain CD63 in their membrane (Cham et al. 1994) but are regarded as specialized secretory granules rather than lysosomes (Cieutat et al. 1998). Azurophil granules undergo limited exocytosis in response to stimulation (Sengelov et al. 1993, Faurschou et al. 2002), their primary role is believed to be killing and degradation of engulfed microbes in the phagolysosome (Joiner et al. 1989).
MPO reacts with H2O2 formed by NADPH oxidase, increasing its toxicity by formation of hypochlorous acid and other chlorination products, tyrosine radicals and reactive nitrogen intermediates which attack the surface of microbes (Klebanoff et al. 2013).
Secondary (specific) granules are peroxidase-negative and rich in antimicrobial substances (Joiner et al. 1989, Rorvig et al. 2012). They are more irregular and elongated in form than azurophil granules (Bainton et al. 1971). This may reflect volume adjustment in azurophil granules, which are known to proteolytically process a significant fraction of the proteins that are targeted to them, while little or no processing and therefore no increase in osmotic activity due to proteolysis has been observed in secondary granules (Borregaard & Cowland 1997). Secondary and tertiary granules have overlapping contents but can be discriminated by their intrinsic buoyant densities when centrifuged on gradient media (Kjeldsen et al. 1994).
Ficoli-1 rich granules are a relatively new fourth neutrophil granule population that is enriched in the microbial lectin ficolin-1. Ficolin-1 is present in tertiary granules, but ficolin-1 rich granules can be differentiated by having low levels of gelatinases and an elevated exocytosis propensity (Rorvig et al. 2009, 2013). The importance of these granules may be to provide rapid release of pattern recognition molecules to activate the lectin complement pathway (Rorvig et al. 2009).
Ficoli-1 rich granules are a relatively new fourth neutrophil granule population that is enriched in the microbial lectin ficolin-1. Ficolin-1 is present in tertiary granules, but ficolin-1 rich granules can be differentiated by having low levels of gelatinases and an elevated exocytosis propensity (Rorvig et al. 2009, 2013). The importance of these granules may be to provide rapid release of pattern recognition molecules to activate the lectin complement pathway (Rorvig et al. 2009).
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
Annotated Interactions
MPO reacts with H2O2 formed by NADPH oxidase, increasing its toxicity by formation of hypochlorous acid and other chlorination products, tyrosine radicals and reactive nitrogen intermediates which attack the surface of microbes (Klebanoff et al. 2013).