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1014 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1015

has been demonstrated to play a protective role in infections against E. Two pattern-recognition molecules, pentraxin 3 and ficolin1,
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coli, Klebsiella pneumoniae, Salmonella typhimurium, and Myco- are found in specific granules and gelatinase granules, respectively.
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bacterium tuberculosis. NGAL has effects not explained by sequester- Pentraxin 3, a member of the long pentraxins family, is synthesized
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ing bacterial siderophores and was shown to worsen the outcome of in myelocytes and metamyelocytes and stored in specific granules of
pneumococcal pneumonia by deactivating macrophages. It is possible neutrophils. Pentraxin-3 binds the complement component C1q and
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that the ability of NGAL to bind endogenous siderophore-like struc- mediates activation of the classical complement cascade. In addi-
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tures and transport iron may explain some of these effects. Nramp1, tion, pentraxin-3 binds K. pneumoniae outer membrane protein A
the cation transporter, was initially identified first in macrophages as (KpOmpA) from Gram-negative bacteria, especially the Enterobacteri-
an essential resistance factor against mycobacterial infection. It is pres- aceae species, and binds Aspergillus fumigatus conidia. Pentraxin-3 was
ent in membranes of both specific and gelatinase-containing neutrophil shown to play a major role in uptake and killing of A. fumigatus conidia
granules. 93,183 by neutrophils in a mouse model. 204,205
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Lysozyme is a cationic antimicrobial peptide of 14 kDa. In agree- Ficolin-1 is present in gelatinase granules. Ficolin-1 binds acety-
ment with its biosynthetic profile, lysozyme is present in all granule lated carbohydrate structures on Gram-positive bacteria and can recruit
subsets, with peak concentrations in specific granules. 100,108 Lysozyme mannose-binding lectin-associated serine proteases (MASPs) and acti-
cleaves peptidoglycan polymers of bacterial cell walls and displays bac- vate the lectin complement cascade. 206
207
tericidal activity toward the nonpathogenic Gram-positive bacteria Arginase-1 is a constituent of gelatinase granules and may par-
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Bacillus subtilis. Lysozyme also binds LPS and reduces cytokine pro- ticipate in regulation of T-cell activities by removing arginine, the essen-
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duction and mortality caused by LPS in a murine model system of septic tial substrate for inducible nitrous oxide synthase. The product, proline,
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shock. In contrast to many neutrophil granule proteins, lysozyme is is essential for collagen synthesis and arginase-1 from neutrophils may
inefficiently targeted to granules and circulates free in plasma in a sub- thus support wound healing.
stantial quantity that reflects the granulopoietic activity. 107,108 Lysozyme Olfactomedin 4, a 65-kDa specific granule protein, forms huge
is also secreted from activated macrophages, and a particular elevated multimers, but only in approximately 25 percent of neutrophils, ranging
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serum level is characteristic of the leukemias with a large proportion of from 5 to 40 percent between individuals and constant in each individ-
monocytes. 189 ual. The functional consequence is unknown. 208,209
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hCAP-18, also known as LL-37 or CAMP, is the only human Membrane proteins of peroxidase-negative granules are shared
89
member of a family of antimicrobial peptides known as cathelicidins. among the subsets of peroxidase-negative granules that can be distin-
Cathelicidins are typically found in peroxidase-negative granules of guished based on their matrix proteins; that is, specific and azurophil
mammalian neutrophils. hCAP-18 is a prominent protein of neu- granules. Two exceptions are Nramp1 and MMP-25, which are both
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trophil specific granules present in equimolar concentrations with present, predominantly in the membrane of gelatinase granules and
lactoferrin. It is also present in plasma at a substantial concentration secretory vesicles. 93,94 Cytochrome b , which is comprised of gp91 phox
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558
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bound to lipoproteins. In general, cathelicidins are proantibiotic pep- and p22 phox , forms the membrane component of the NADPH oxidase and
tides that share a common and highly conserved 14-kDa N-terminal is a prominent membrane protein of peroxidase-negative granules. 81,210
region known as the cathelin region, whereas the C-terminal regions It codistributes with the major β -integrin of neutrophils CD11b/CD18,
2
vary extensively among the different cathelicidins. The C-terminal with the major segment in specific granules, some in gelatinase gran-
peptides must be liberated from the cathelin domain by proteolysis ules, and some in secretory vesicles. Secretory vesicles are rapidly mobi-
to become antibacterial. In most species this is carried out by elastase, lized, and even though only 15 percent of the total cytochrome b and
588
but in human neutrophils this is done by proteinase 3 from azurophil CD11b localizes to secretory vesicles, this is the fraction that is primar-
granules. The liberated C-terminal peptide is known as LL-37. 90,190 Like ily translocated to the plasma membrane during neutrophil diapesis. 66,32
several other neutrophil proteins, hCAP-18 is formed by cells in other Hv1is a voltage-gated proton channel situated in the plasma membrane
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tissues, particularly epithelial cells. 90,193–195 It is constitutively expressed and membranes of peroxidase-negative granules. Hv1 associates with
in the testis and present in semen. Here, the activating protease is gas- nascent phagosomes, and neutralizes the negative charge induced by
tricin, a prostate protease that is active at low pH. This cleaves hCAP-18 transport of electrons by the NADPH oxidase. 212,213 The CD66 antigens
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to ALL-38, which has the same antibacterial spectrum as LL-37. The found in the membrane of specific granules may play a role as bacte-
cathelin part, which is released has some protease inhibitory activity by rial receptors (galectin receptors) and generate signals to activate the
itself. The LL-37 stimulates neutrophil, monocyte, and T-cell chemo- NADPH oxidase. 214,215
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taxis via the formyl peptide receptor-like-1. In addition, hCAP-18/
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LL-37 has angiogenic and endotoxin-neutralizing properties. 200 STIMULUS-RESPONSE COUPLING BY NEUTROPHILS
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Three MMPs have been identified in neutrophils: neutrophil
collagenase (MMP-8,75 kDa), which is localized to specific gran- Stimulus-response coupling by neutrophils has been the subject of
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ules, gelatinase (MMP-9,92 kDa), which resides predominantly intense research for many years. This work has been fruitful in illu-
in gelatinase granules, 78,202 and leukolysin (MT6-MMP/MMP-25,56 minating some of the underlying causes of defects in cell activation.
kDa), which is distributed among specific granules (approximately Studies of neutrophil degranulation and oxidative metabolism have
10 percent), gelatinase granules (approximately 40 percent), secre- also revealed transduction mechanisms common to a wide variety of
tory vesicles (approximately 30 percent), and the plasma membrane other important secretory cell types, thereby greatly expanding the
(approximately 20 percent) of resting neutrophils. 94,203 The MMPs relevance of this work. This chapter considers next our current under-
are stored as inactive proforms that are proteolytically activated standing of the activation process, which is shown schematically in
following exocytosis. Together, the MMPs are capable of degrading Fig. 66–4.
major structural components of the extracellular matrix, including
collagens, fibronectin, proteoglycans, and laminin, and they are RECEPTOR–LIGAND INTERACTIONS
believed to be of central importance for the degradation of vascu- Formyl Peptide Receptor
lar basal membranes and interstitial structures during neutrophil Neutrophil responses can be evoked by a variety of particulate
extravasation and migration. and soluble stimuli. Opsonized particles, immune complexes, and

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