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CHAPTER 65 COMPOSITION AND METABOLISM OF NEUTROPHILS

CHAPTER 65 COMPOSITION AND METABOLISM OF NEUTROPHILS
Williams Hematology

CHAPTER 65 COMPOSITION AND METABOLISM OF NEUTROPHILS

ERNEST BEUTLER

Composition of Neutrophils

Water and Electrolytes

Carbohydrates

Amino Acids, Peptides, and Proteins

Lipids

Nucleotides and Nucleic Acids

Vitamins and Cofactors
Metabolism of Neutrophils

Carbohydrate Metabolism

Dna and Rna Metabolism

Protein

Nucleotide Metabolism

Lipid Metabolism
Chapter References

Neutrophils are highly specialized differentiated cells, and details of their specialized metabolic pathways are given in Chap. 67 and Chap. 72. This chapter deals with the composition of granulocytes, their content of water, electrolytes, carbohydrates, amino acids, peptides, proteins, lipids, nucleic acids, vitamins, and cofactors. The housekeeping metabolic pathways of neutrophils for aerobic and anaerobic energy metabolism, and DNA, nucleotide, and lipid metabolism are also reviewed.

Acronyms and abbreviations that appear in this chapter include: ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; GM-CSF, granulocyte-macrophage colony-stimulating factor; 5-HETE, 5-hydroxyeicosatetraenoic acid; 5-HPETE, 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid; 15-HPETE, 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid; LAP, leukocyte alkaline phosphatase; LTA4, leukotriene A4; PAF, platelet-activating factor; SE, standard error; SRS, slow-reactivity substance.

COMPOSITION OF NEUTROPHILS
Many of the measurements of the composition of leukocytes were performed at a time when those carrying out the analyses did not appreciate that the white cells of the blood were heterogeneous in origin and function. Thus, many of the data pertain to leukocytes as a whole, not to isolated neutrophils. Often, granulocytes were studied rather than neutrophils. In many cases, however, the content of analytes is similar in neutrophils and other white blood cells, and the best data available are presented here and expressed as values in neutrophils, recognizing that in some cases the values may be distorted by the presence of other leukocytes in the mixtures analyzed.
WATER AND ELECTROLYTES
Approximately 82 percent of the leukocyte weight is water.1 There is a remarkable paucity of data regarding the electrolyte content of neutrophils. The often quoted 1929 study of Endres and Herget1 was carried out on mixed leukocytes from the blood of horses obtained at a slaughterhouse. They found an average of 2610 mg (113 mmol) sodium, 889 mg (22.7 mmol) potassium, 72 mg (1.8 mmol) calcium, 10.3 mg (0.18 mmol) iron, 2487 mg (70.2 mmol) chloride, and 299 mg (9.65 mmol) inorganic phosphate per liter of leukocytes. The copper content of neutrophils has been reported to average 4.69 nmol/109 cells,2 zinc 109.2 nmol/109 cells2 and 50.16 nmol/109 cells,3 and magnesium 3.11 fmol/cell.4 There is little selenium in neutrophils, the median concentration having been reported as less than 0.0075 µmol/109 cells.5 Otherwise, electrolyte determinations on human leukocytes appear to have been limited to leukemic cells and to pus.6
CARBOHYDRATES
The rate of metabolism of glucose by neutrophils is affected by insulin in diabetics but not in normal subjects.7,8 The neutrophil is particularly rich in glycogen. The concentration of this complex polysaccharide has been reported to average 7.36 mg/109 cells.9,10 and 11
AMINO ACIDS, PEPTIDES, AND PROTEINS
The concentrations of most amino acids are higher in neutrophils than is the surrounding plasma.12 The amino acid concentration in neutrophils is summarized in Table 65-1. The reduced glutathione content of neutrophils is 9.8 nmol per 107 cells.13

TABLE 65-1 UNBOUND AMINO ACID CONCENTRATIONS IN LEUKOCYTES (LYMPHOCYTES INCLUDED)

The protein content of the neutrophil is 74.2 ± 3.1 (mean ± 1 SE) mg/109 cells.14 These proteins include those of the structural matrix of the neutrophil; proteins required for its locomotion, chemotactic properties, and adhesiveness; and the many granule proteins with bactericidal, hydrolytic, and inflammatory functions. These proteins are described in detail in Chap. 64, Chap. 67, and Chap. 72.
LIPIDS
As in other cells, the plasma membrane and the membranes of the intracellular organelles are rich in lipids. Five percent of the wet weight of neutrophils is lipid, which is distributed among various classes, as shown in Table 65-2.15,16,17,18 and 19 The rare polyphosphoinositides are of special interest as sources of inositol 1,4,5-trisphosphate (a calcium-releasing mediator) and diacylglycerol (which activates protein kinase C).20,21 The main glycolipid of neutrophils is lactosylceramide.22

TABLE 65-2 LIPID COMPOSITION OF NEUTROPHILS

NUCLEOTIDES AND NUCLEIC ACIDS
The levels of nucleotides in the neutrophils are summarized in Table 65-3.23,24

TABLE 65-3 NUCLEOTIDES IN LEUKOCYTES (LYMPHOCYTES INCLUDED)

Neutrophils contain all the forms of RNA needed for protein synthesis: transfer RNA, ribosomal RNA, and messenger RNA.27,28 The DNA content of neutrophils is identical to that of all other haploid cells, at 0.7 pg DNA phosphorus per cell.29
VITAMINS AND COFACTORS
The average folic acid content of packed leukocytes of normal subjects was 0.1 µg/ml of packed leukocytes, and about 20 percent of this was free and the remainder conjugated.30 The cocarboxylate content is 340 µg/1011 cells,31 pyridoxal phosphate 0.24–0.38 ng/106 cells,32 thiamine 67.5 ± 4.1 µg/100 ml,33 ascorbic acid 16.5 ± 5.1 mg/100 ml,34 and folate 92 ng/ml.35
METABOLISM OF NEUTROPHILS
CARBOHYDRATE METABOLISM
GLYCOLYSIS
The Main Glycolytic (Embden-Meyerhoff) Pathway The main energy-producing pathway in the neutrophil is glycolysis, resulting in the conversion of glucose to lactate.36,37 and 38 When intact or homogenized leukocytes are incubated with glucose uniformly labeled with 14C, about 80 percent of the radioactivity is recovered in lactic acid. Glycolysis is inhibited by cortisol.7 The activities of the glycolytic enzymes of neutrophils are summarized in Table 65-439,40 and 41; in some cases the conditions under which the neutrophils are disrupted have a significant effect on the activities measured.40 Hexokinase is the rate-limiting enzyme of glycolysis in normal neutrophils.37 The rate of glycolysis is not altered during phagocytosis,38 but ATP levels, normally 1.9 nmol/106 cells, fall to 0.8 nmol/106 cells. Both the glycogen stores of neutrophils and the glucose of the plasma can serve as the source of glucose. Galactose, mannose, and fructose can also be metabolized by leukocytes.43

TABLE 65-4 GLYCOLYTIC AND RELATED ENZYME ACTIVITIES IN NEUTROPHILS

The Hexose Monophosphate Shunt Pathway Neutrophils also metabolize glucose by way of the hexose monophosphate shunt,44,45 and 46 and this accounts for some of the oxygen consumption of the cells. In resting cells, the amount of glucose metabolized via this route amounts to only 2 to 3 percent of the total glucose consumed by the cell.45,46 and 47 The operation of the hexose monophosphate shunt, however, is of special importance to the neutrophil, because it is this pathway that provides the NADPH needed for the generation of microbicidal oxidants (see Chap. 67).
Glycogen Metabolism Neutrophils contain a large quantity of glycogen (see above), arising mostly from glucose; there is little net synthesis from substrates at the triose phosphate level. Glycogen turnover increases when these cells are deprived of glucose, especially if they are engaged in phagocytosis, but resynthesis occurs when adequate glucose is added.38,48,49 During phagocytosis by glucose-starved cells, glycogen phosphorylase activity rises, but phosphorylase kinase and glycogen synthase levels remain unchanged.48 Glycogen first appears in myelocytes and increases with cell maturation.50
OXIDATIVE METABOLISM
Neutrophils consume 0.15 µmol oxygen per 107 cells in the absence of glucose and 0.015 µmol oxygen per 107 cells in the presence of glucose.51 Oxygen consumption by neutrophils is influenced by a wide variety of physiologic and pathologic stimuli.52 In addition to phagocytosis (see Chap. 67), these include thyroid hormone, CO2 tension,53 glucose concentration,54 serum,55 pyrogens,56 complement components, chemotactic peptides, and immune complexes.57 A number of chemicals depress neutrophil respiration, including saponin, thiouracil, chloramphenicol, cyanide, fluoroacetate, malonate, and p-hydroxymercuribenzoate. Other compounds, such as ascorbic acid and dinitrophenol, increase O2 consumption.52
Few mitochondria are found in mature neutrophils,58 and mitochondrial respiration accounts for only 5 percent of the glucose consumed by the neutrophil.59,60 Because of the efficiency of mitochondrial ATP synthesis, however, it furnishes nearly half the ATP generated by the cell. The following Krebs cycle enzymes have been detected in leukocytes: isocitric dehydrogenase, aconitase, fumarase, and malic dehydrogenase.61,62 In addition, the metabolically related enzymes glutamate-oxaloacetate aminotransferase and glutamate-pyruvate aminotransferase are also found in neutrophils.63 The four enzymes necessary for gluconeogenesis were not detected in leukocytes.
DNA AND RNA METABOLISM
DNA polymerase is most active in early neutrophil precursors.64 Activity diminishes with cell maturation and is barely detectable in mature cells. Consistent with this finding, the myelocyte is the most mature neutrophil precursor that can still incorporate thymidine into DNA and undergo mitosis.65,66 Like other cells, neutrophils synthesize RNA using DNA as a template.67,68 Earlier studies using the incorporation of [14C]uridine into RNA as a measure of RNA synthesis were difficult to interpret because they were carried out with mixed populations of cells.67 However, Northern blotting has indicated unequivocally that neutrophils have the capacity to synthesize specific messenger RNA.69,70
PROTEIN
Mature neutrophils and neutrophil precursors incorporate labeled amino acids into proteins68,71,72,73 and 74 and have been shown to synthesize fibronectin.70 Protein synthesis also seems to play a role in receptor recycling by neutrophils.75 Once proteins are synthesized, they undergo extensive posttranslational modification and are sorted into the appropriate organelle.76
NUCLEOTIDE METABOLISM
BIOSYNTHESIS
Many of the studies on nucleotide biosynthesis have been conducted in mixed cell populations. Conclusions from such studies regarding nucleotide biosynthesis in neutrophils must be regarded as provisional. Leukocytes are capable of de novo biosynthesis of pyrimidines. The enzymes of pyrimidine biosynthesis (aspartate carbamyltransferase, dihydroorotase, dihydroorotic dehydrogenase, and orotidylic decarboxylase) are found in normal leukocytes (predominantly neutrophils).77 The failure to demonstrate 14C-glycine incorporation into the acid-insoluble nucleotide pool in normal leukocytes suggested that, in contradistinction to their ability to carry on pyrimidine biosynthesis de novo, these cells are incapable of the earlier steps of purine synthesis.78 In addition to de novo pyrimidine synthesis, ribo- and deoxyribonucleotides can also be formed via the “salvage” pathway through the kinase-catalyzed interaction of ATP with nucleosides and deoxynucleosides (cytidine, uridine, deoxycytidine, deoxyuridine, and thymidine).79,80,81,82,83 and 84 The enzyme that catalyzes the conversion of ribonucleotides to deoxyribonucleotides, however, has not been detected in normal neutrophils.
CATABOLISM
The presence of ribonuclease and deoxyribonuclease in lysosomal granules of leukocytes85,86 suggests that these organelles are involved in the breakdown of exogenous and/or endogenous nucleic acids. Ribonuclease activity is 10 times higher in mature neutrophils than in blast forms.87 In addition, nucleotidases,88 several isoenzymes of acid phosphatase,89 and a nucleoside deaminase have been described.83 Mature neutrophils, however, contain only very low levels of 5′-nucleotidase and adenosine deaminase.
One of the most extensively investigated neutrophil enzymes is LAP. Leukocyte alkaline phosphatase is a zinc-containing phosphomonoesterase with a pH optimum near 10 that catalyzes the hydrolysis of a wide variety of phosphoester substrates.90,91 The activity of LAP, which is limited to the neutrophilic series, first appears in myelocytes and rapidly increases with maturation of the cell to the segmented polymorphonuclear neutrophil.92 Glucocorticoids markedly increase the activity in normal leukocytes, probably by induction of the enzyme, which may explain the high LAP activity observed during infections.93 Although the in vivo function of LAP remains uncertain, the assay of this activity has found many clinical applications. Marked changes in LAP activity are observed in chronic myelocytic leukemia and other myeloproliferative disorders, as well as in certain other conditions, including idiopathic thrombocytopenic purpura, infectious mononucleosis, aplastic anemia, and sarcoidosis.94,95,96 and 97
CYCLIC NUCLEOTIDES
Cyclic 3′,5′-cAMP is present in the human neutrophil.98 This “second messenger” is involved in the activation of leukocyte glycogen phosphorylase. The synthesis of cAMP is catalyzed by adenyl cyclase and its degradation by cAMP phosphodiesterase, both of which are found in normal neutrophils.89 The accumulation of cAMP in the leukocyte is stimulated by epinephrine, prostaglandin E, and adenyl cyclase.99,100 A transient rise in cAMP levels (duration 2–5 min) is also seen after exposure of neutrophils to inflammatory agonists such as formylated oligopeptides or immune complexes, but the cyclic nucleotide appears to have only a minor effect on neutrophil function.101 The cytosol of neutrophils contains a protein kinase that is stimulated by cAMP.102 These cells also contain histone phosphatases, which dephosphorylate the product of the protein kinase reaction.103 A reduced responsiveness of b-receptor function for isoproterenol (Isuprel) in leukocytes of patients suffering from acute bronchial asthma has been reported.104,105 In asthmatic patients in remission, this response was within normal limits.106
There has been little study of cGMP in neutrophils; exposure of neutrophils to inflammatory mediators caused no change in their levels of cGMP.101
LIPID METABOLISM
Early studies revealed that lipid biosynthesis, as measured by the incorporation of [14C]acetate, takes place in neutrophils. Two-thirds of the radioactivity was incorporated into neutral lipids and the remainder into phospholipids.107 Neutrophils also incorporated [2-14C]acetate and [2-14C]mevalonate into squalene but not into sterols.108 Younger neutrophils, as found in infection, had lower rates of incorporation of labeled acetate into lipids.109
The phosphatidic acid pathway incorporating fatty acids into neutral lipids is operative in these cells.110 The incorporation of fatty acids into lysophospholipids also occurs in neutrophils, leading to the formation of diacylglyceryl phosphocholine and diacylglyceryl phosphoethanolamine.111 Phagocytosis is accompanied by a threefold increase in the acylation of exogenous lysolecithin, leading to a net increase in phospholipid. PAF is synthesized by replacing the 2-acyl group (usually arachidonate) in 1-alkyl-2-acylglycerol phosphocholine with acetate.112
Acetyl CoA carboxylase, the first enzyme required for the synthesis of long-chain fatty acids, has been found in myeloblasts but not in mature neutrophils. The latter cells, however, retain the capability of elongating the chains of preformed fatty acids.113
A number of lipolytic activities are present in human neutrophils. One of these, a triacylglycerol acylhydrolase acting on lipoprotein and chylomicron substrates, has been purified.114 A cholesterylesterase activity is also associated with this enzyme. Fatty acid ester hydrolases have been described.115 Several phospholipases are found in neutrophils.116,117 Their activation occurs upon stimulation of the neutrophil, leading to the production of signal-transducing chemicals and lipid mediators.
Arachidonic acid is the precursor of a group of lipid mediators that play important roles in the regulation of a wide range of biological responses.118 It is released from phospholipids by phospholipase A2,119 activated by the exposure of neutrophils to such stimuli as opsonized zymosan, calcium ionophore, or chemotactic factors.119,120 and 121 Lipid mediators are then produced from the liberated arachidonic acid by either a cyclooxygenase- or a lipoxygenase-catalyzed oxidation (Fig. 65-1). In the neutrophil, oxidation by lipoxygenase exceeds that by cyclooxygenase,112,119,122,123 and it may be that the arachidonic acid activates the lipoxygenase.124

FIGURE 65-1 Production of lipid mediators from arachidonic acid. Above, production of thromboxane A2 and prostacyclin. Below, production of leukotrienes A4, B4, and C4.

Cyclooxygenase (prostaglandin synthetase) catalyzes the conversion of arachidonic acid into the cyclic endoperoxides PGG2 and PGH2, which in turn are isomerized into the prostaglandins PGE2, PGD2, and PGF2.118 PGE2 is a major mediator of the inflammatory process, dilating and permeabilizing small blood vessels to give rise to edema and erythema.104 PGH2 may also be converted to the unstable vasoconstrictor thromboxane A2, which rapidly hydrolyzes to thromboxane B2,125 which is vasoinactive but chemotactic.
The most important lipoxygenase in neutrophils is 5-lipoxygenase.126,127 This enzyme catalyzes the oxidation of arachidonic acid to 5-HPETE and its subsequent conversion to leukotriene A4 (LTA4), the unstable parent compound of the leukotrienes, a group of lipid tbmediators with major effects on the inflammatory process (Fig. 65-2). nbLTA4 may add glutathione to form LTC4,128 whose peptide bonds may subsequently be successively hydrolyzed to yield LTD4, containing a cysteine-glycine dipeptide, and LTE4, containing cysteine only. Together, leukotrienes C4, D4, and E4 constitute the activity known formerly as the SRS of anaphylaxis.129,130,131 and 132

FIGURE 65-2 Structure and formation of the cysteinyl leukotrienes. Leukotriene C4, produced by the reaction of glutathione with leukotriene A4, as shown in Fig. 65-1, is converted to leukotrienes D4 and E4 by the successive removal of the terminal amino acids from the peptide chain. GGTP, g-glutamyl tripeptidase.

Alternatively, LTA4 may be hydrolyzed to generate LTB4,133,134 a potent chemotactic factor and neutrophil activator.135,136 LTB4 production by neutrophils is induced by a number of stimuli137,138,139 and 140 whose effects on its production are further regulated by the growth factor GM-CSF.138,139,140 and 141 LTB4 is inactivated by neutrophil P450 cytochrome(s), which catalyze successive oxidations at the x omega position to yield 20-OH-LTB4, LTB4-20-carboxaldehyde, and finally LTB4-20-carboxylic acid.142,143 and 144
The enzymes responsible for leukotriene production can also oxidize C20-D3 (c-linolenic) and C20-D5 fatty acids, leading to the LTA3 and A5 series of leukotrienes. Because they are less potent than the A4 series of leukotrienes, the A3 and A5 leukotrienes can act as anti-inflammatory agents, partially antagonizing the effects of the A4 series.145,146
The hydroperoxyl group of 5-HPETE is sometimes reduced to a hydroxyl group before conversion to LTA4 can take place. This reduction yields a major product, 5-HETE,147 and a minor product, 12-HETE (an isomer of 12,L-hydroxy-5,8,10,14-eicosatetraenoic acid). Both 5- and 12-HETE have chemotactic properties and stimulate the release of lysozyme from neutrophils.148
Neutrophils also contain a 15-lipoxygenase that converts arachidonic acid to 15-HPETE.126 Subsequent oxidation of 15-HPETE by 5-lipoxygenase followed by hydrolysis of the resulting epoxide gives rise to the lipoxins, a family of C-20 fatty acids containing four conjugated double bonds and three hydroxyl groups.128,148 These, too, are inflammatory mediators, with effects that are similar in general but different in particular from those of the leukotrienes.
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Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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