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CHAPTER 66 NEUTROPHIL STRUCTURE

DISORDERS OF NEUTROPHIL AND FUNCTION

FUNCTION CHEMOTAXIS AND MOTILITY
The similarity between neutrophil locomotion and that of amebas
was noted long ago. Neutrophils respond to spatial gradients of che-
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motaxins with differences in concentration of chemotaxin of as little
2
Niels Borregaard as 1 percent across the cell, although there has been contention as to
whether chemotaxis also requires temporal, as well as spatial, sensing.
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Even with populations of cells as “homogenous” as neutrophils, a broad
range of responsiveness is found. During locomotion toward a che-
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SUMMARY motactic source, neutrophils acquire a characteristic asymmetric shape
(Fig. 66–1). In the front of the cell is a pseudopodium, referred to as the
The neutrophil circulates in blood as a quiescent cell. Its main function as a lamellipodium, that advances before the body of the cell containing the
phagocytic and bactericidal cell is performed outside the circulation in tissues nucleus and the cytoplasmic granules. At the rear of the moving cell
where microbial invasion takes place. Neutrophil function is traditionally viewed is a knob-like tail, the uropod. The lamellipodium undulates or “ruf-
as chemotaxis, phagocytosis, and bacterial killing. Although these conceptionally fles” as the neutrophil moves, at a rate of up to 50 μm/min. The mem-
2+
represent distinct entities, they are functionally related, and rely to a large extent brane lipids also flow during locomotion, and enhanced cytosolic Ca is
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on the same intracellular signal transduction mechanisms that result in localized observed along the membrane margin. The lamellipodium, which is very
rises in intracellular Ca , changes in organization of the cytoskeleton, assembly thin, forms immediately when the cell encounters a gradient of chemotactic
2+
of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase from its factor. As the cell moves, the cytoplasm behind the lamellipodium streams
cytosolic and membrane integrated subunits, and fusion of granules with the forward, almost obliterating it. At this point, some granules appear to contact
the cell periphery and release granule contents in response to chemotactic
phagosome or neutrophil plasma membrane. Clinical disorders of the neutrophil agents. The lamellipodium extends again and the process repeats itself. A
may arise from impairment of these normal functions. The clinical presenta- flow of cortical materials, composed particularly of actin filaments, has been
tion of a patient who has a qualitative neutrophil abnormality may be similar proposed to account for chemotaxis as well as other cellular movements.
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to that of one who has an antibody, complement, or toll-like receptor disorder. This may also account for changes in cell viscosity. Polarity and movement
In general, evaluation for phagocyte cell disorders should be initiated among is orchestrated by the cytoskeleton through signals generated from receptor
those patients who have at least one of the following clinical features: (1) two or associated G-proteins in an intricate network that regulates both direction
more systemic bacterial infections in a relatively short time period; (2) frequent, and intensity of movement. 8–11
serious respiratory infections, such as pneumonia or sinusitis, or otitis media, or
lymphadenitis; (3) infections present at unusual sites (liver or brain abscess); and INGESTION
(4) infections associated with unusual pathogens (e.g., Aspergillus pneumonia,
disseminated candidiasis, or infections with Serratia marcescens, Nocardia species, or When a neutrophil comes in contact with a particle, the pseudopodium
Burkholderia cepacia). flows around the particle, its extensions fuse, and it thereby encom-
passes the particle within the phagosome. The ingestion phase can be
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Acronyms and Abbreviations: ADP, adenosine diphosphate; ARF, ADP-ribosylation toll/interleukin-1 receptor domain containing adaptor protein; MAPK, micro-
factor; ASC, apoptosis-associated speck-like protein with a caspase recruitment tubule-associated protein kinase; MBL, mannose-binding lectin; MMP, matrix
domain; ATPase, adenosine triphosphatase; BPI, bacterial permeability-increasing metalloproteinase; MPO, myeloperoxidase; MyD88, myeloid differentiation factor
protein; cAMP, cyclic adenosine monophosphate; cANCA, cytoplasmic antineu- 88; NADPH, nicotinamide adenine dinucleotide phosphate (reduced form); NBT,
trophil cytoplasmic antibody; CARD, caspase activation and recruitment domain; nitroblue tetrazolium; NEM, N-ethylmaleimide; NET, neutrophil extracellu-
c/EBP, CCAAT/enhancer binding protein; CGD, chronic granulomatous disease; CHS, lar trap; NF-κB, nuclear factor-κB; NGAL, neutrophil gelatinase-associated
Chédiak-Higashi syndrome; DAG, diacylglycerol; DOCK8, dedicator of cytoki- lipocalin; NK, natural killer; NSF, N-ethylmaleimide–sensitive fusion protein;
nesis 8; ESAM, endothelial cell-selective adhesion molecule; FAD, flavin adenine NSP4, neutrophil serine protease 4; PA, phosphatidic acid; PAF, platelet-acti-
dinucleotide; FMF, familial Mediterranean fever; fMLP, formyl-methionyl-leucyl- vating factor; PECAM, platelet endothelial adhesion molecule; phox, phagocyte
phenylalanine; G6PD, glucose-6-phosphate dehydrogenase; GDP, glucose diphos- oxidase; PI3K, phosphatidylinositol 3′-kinase; PIP , phosphatidylinositol-
1
phate; GPI, glycosylphosphatidylinositol; GTP, guanosine triphosphate; GTPase, 4-monophosphate; PIP , phosphatidylinositol-4,5-bisphosphate; PKC, protein
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guanosine triphosphatase; H O , hydrogen peroxide; HBP, heparin-binding protein; kinase C; PLC, phospholipase C; PLD, phospholipase D; PLS, Papillon-Lefèvre
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HETE, hydroxyeicosatetraenoic acid; HLA, human leukocyte antigen; HNP, human syndrome; PSGL, P-selectin glycoprotein ligand; SGD, specific granule defi-
neutrophil peptide (synonym: defensin); ICAM, intercellular adhesion molecule; ciency; SH3, Src homology 3; sLe , sialyl Lewis X; SNAP, soluble NSF attachment
x
IFN, interferon; Ig, immunoglobulin; IL, interleukin; IP , inositol triphosphate; protein; SNARE, SNAP receptor; TIR, toll/interleukin-1 receptor; TLR, toll-like
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ITAM, immunoreceptor tyrosine-based activation motif; JAMs, junctional receptors; 7TMRs, seven trans-membrane–spanning domain proteins; TNF,
adhesion molecule A, B, and C; LAD, leukocyte adhesion deficiency; LFA-1, tumor necrosis factor; TRAM, TRIF-related adaptor molecule; TRAPS, tumor necrosis
leukocyte function-associated antigen-1; LPS, lipopolysaccharide; LSP-1, lym- factor receptor–associated periodic syndrome; TRIF, TIR domain-containing adap-
phocyte-specific protein-1; LTB , leukotriene B ; Mal/TIRAP, MyD88-adaptor-like/ tor inducing interferon (IFN)-β; VAMP-2, vesicle-associated membrane protein-2.
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Kaushansky_chapter 66_p1005-1042.indd 1005 9/21/15 10:47 AM