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1010 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1011

processed. The MMPs of peroxidase-negative granules are stored as a Targeting by Biosynthetic Timing
proform, as is the major bactericidal protein hCAP-18. 89,90 No major The extreme heterogeneity of neutrophil granules and their individual
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differences have been identified in the content of membrane proteins control of exocytosis can be explained simply by timing of their biosyn-
of the peroxidase-negative granule subsets. All contain the flavocy- thesis (Fig. 66–3). Granule proteins are synthesized during myelopoiesis
tochrome p22 phox /gp91 phox complex that is part of the nicotinamide from myeloblasts to band cells and segmented neutrophils in the mar-
adenine dinucleotide phosphate (NADPH) oxidase, and all contain the row. 75,76,98 The window of biosynthesis of each granule protein is highly
major β -integrin α β —and these are even shared with the membrane controlled by combinations of transcription factors that change as the
M 2
2
of secretory vesicles. 32,91,92 The divalent cation transporter Nramp1 is cells differentiate and mature. 99,100 If all granule proteins are targeted to
localized only to gelatinase granules, and the membrane MMP leukol- granules during synthesis, the content of newly formed granules would
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ysin (MMP-25) is shared between gelatinase granules and secretory change as the cell matures because the profile of biosynthesis changes.
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vesicles. However, the subsets differ markedly in their propensity for A global view of the change in transcriptional activity of neutrophil
exocytosis. Following neutrophil stimulation, gelatinase granules are precursors during maturation in the marrow confirmed the association
exocytosed to a larger extent than granules containing both lactoferrin between granule localization and transcriptional activity. This simple
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and gelatinase, and these are more readily mobilized than granules con- mechanism largely explains the heterogeneity of granules and their
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taining lactoferrin but lacking gelatinase. These, in turn, are mobilized contents, but it does not account for the differences in exocytotic rates
more readily than peroxidase-positive granules. 62,66,79,87,95 This organiza- among individualized subsets. By timing the biosynthesis of the pro-
tion of granule subsets with different content and different set points to teins essential for fusion 103,104 to granule membranes during maturation,
trigger exocytosis allows the neutrophil to mobilize MMPs and integ- it is possible to regulate the rates of exocytosis. Indeed, the v-SNARE
rins necessary for movement through the basal membrane and tissue (SNAP receptor), vesicle-associated membrane protein (VAMP)-2
before the bactericidal peptides and serine protease are called to play, is present in a higher density on gelatinase granules than on specific
but it puts an enormous task on the organization of the biosynthetic granules and is most highly expressed on secretory vesicles, 105,106 which
apparatus to secure that the right granule proteins are targeted to the correlates with the ease of releasing granule subsets from the neutrophil
granules with a given trigger for exocytosis. following activation.
The content of isolated granules has been mapped by proteome
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analysis. High-resolution mass spectrometry has identified 1300 Sorting between the Constitutive and Regulated Exocytotic
proteins associated with neutrophil granules, plasma membranes and Pathway
secretory vesicles and confirmed that localization is largely determined Although the sorting by timing can explain the granule heterogeneity
by time of biosynthesis. 97 of neutrophil granules, it does not provide any clues to the mechanisms

Figure 66–3. Formation of granule subsets during myelopoiesis and regulation of granule protein transcription. Difference in the appearance
and disappearance of transcription factors regulate the individual window of granule protein gene transcription and translation into protein that is
targeted to forming granules, explaining the heterogeneity of neutrophil granules.

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