Chapter 3 : Neutrophils: the Power Within

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Neutrophils form the major type of leukocytes in peripheral blood, with counts ranging from 40 to 70% of the leukocytes under normal conditions. Neutrophilic granulocytes protect the human body against bacterial and fungal infections. For this purpose, neutrophils are equipped with a machinery to sense the site of an infection, to crawl toward the invading microorganisms, and to ingest and kill them. Neutrophils mature in the bone marrow in about 2 weeks, a process in which the myeloid-specific growth factors granulocyte colony stimulating factor (G-CSF) and granulocyte monocyte CSF (GM-CSF) play an important role. The bone marrow comprises a reserve pool of mature neutrophils of about 20 times the number of neutrophils in the circulation. Neutrophil elastase is normally synthesized in the myeloblasts as an inactive proenzyme but is packaged in the azurophil granules in its active form. Many of the chemotaxins involved in granulocyte movement are small proteins of about 60 to 100 amino acids, very homologous in structure, known as the chemokine superfamily. The processes of adhesion of neutrophils to endothelial cells and subsequent diapedesis take place at postcapillary venules. Extravasation is a multistep process involving adhesion molecules and activating agents that act as (pro-) inflammatory mediators. The chapter also talks about sensing danger signals, phagocytosis and microbicidal activity, and neutrophil apoptosis. Neutrophils are very useful but also very dangerous tools to protect the host from bacterial and fungal infections.

Citation: Kuijpers T, Roos D. 2004. Neutrophils: the Power Within, p 45-70. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch3

Key Concept Ranking

Innate Immune System
Tumor Necrosis Factor alpha
Adaptive Immune System
Acute Respiratory Distress Syndrome
Complement Receptor Type 1
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Image of FIGURE 1

Neutrophil life span and stages of maturation. (Top) Schematic representation of the maturation of the myeloid lineage and the formation of granular structures during neutrophil development. In the promyelocyte stage, the azurophil granules (in light gray) are formed, whereas the specific granules (in medium gray) are formed in the myelocytic stage. Later, the tertiary granules and secretory granules (in dark gray) are generated.The stages of differentiation during which the various granules and their content are being formed are indicated by the arrows and main proteins underneath. (Bottom) Transcription factors involved in the synthesis and expression of key molecules and structures for neutrophil development and function. PU.1 and C/EBPα are important for expression of the G-CSFR and the α chain of the IL-6R, adhesion molecules such as CD62L (L-selectin) and CD11b (α chain of β integrin CD11b/CD18 or Mac-1/CR3), and the main azurophil granular proteins MPO and serine proteases such as elastase. C/EBPє is important for the expression of the specific granules and their contents, and for the main membrane-associated β subunit of the NADPH oxidase system gp91. The transcription factor(s) involved in the expression of one of the most abundantly expressed surface molecules on neutrophils, i.e., FcγRIIIb, remains to be identified.

Citation: Kuijpers T, Roos D. 2004. Neutrophils: the Power Within, p 45-70. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch3
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Image of FIGURE 2

Transmigration of a neutrophil across the vascular endothelium in different steps. The steps are believed to take place in consecutive order, in which different adhesion molecules take part. The first selectin-driven rolling is followed by integrin-mediated firm adhesion. Final transmigration of phagocytes proceeds partly by integrin-mediated processes and several adhesion molecules of the Ig-like supergene family among which are ICAMs, VCAM, CD31/PECAM-1 (platelet-endothelial cellular adhesion molecule), and the recently described junctional adhesion molecule-1 ( JAM-1) on endothelial cells. The relative contributions of these various molecules as active receptors and passive ligands may differ for neutrophils, eosinophils, basophils, or monocytes to migrate through monolayers of endothelial or epithelial cells.VLA, very late antigen; EC, endothelial cell; PSGL-1, P-selectin-glycoprotein ligand-1.

Citation: Kuijpers T, Roos D. 2004. Neutrophils: the Power Within, p 45-70. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch3
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Image of FIGURE 3

TLR signaling cascade. TLRs, which recognize pathogen-associated molecular patterns, and members of the proinflammatory IL-1R family, share homologies in their cytoplasmic domains called Toll/IL-1R/plant R gene homology (TIR) domains. Human TLR4 and TLR2 recognize LPS or LTA and bacterial PGNs, respectively. Intracellular signaling mechanisms mediated by TIRs are similar, with MyD88 and tumor receptor-associated factor 6 (TRAF6) having critical roles. Ubiquitination through transforming growth factor betaactivated kinase-1 (TAK1) and TAK-binding protein (TABs) activates TRAF6 to form the platform required for TAK1-mediated activation of inhibitor of NF-κB kinase (IKK). This complex consists of three enzymatic subunits (IKKα and -β) and a stabilizing subunit (NEMO or IKKγ) and acts as a serine kinase inhibitor of NF-κB (IκB). Signal transduction between MyD88 and TRAF6 is known to involve the serine-threonine kinase IRAK-1 and homologous proteins, IRAK-2, -4, and IRAK-M(yeloid). IRAK-4 is essential for responsiveness to viral and bacterial challenges, whereas IRAK-M downregulates the IRAK-mediated activation in phagocytes and dendritic cells. In contrast to the activation through ubiquitination of TRAF6, the phosphorylation and ubiquitination of IκB lead to its proteasome-mediated breakdown after release of a now activated, dimerized NF-κB. Although MyD88-mediated responses are the main way for TLR signaling, TLR4-associated TIR-containing adaptor protein (TIRAP) can bypass MyD88 by direct activation of a double-stranded RNA-dependent protein kinase (PKR) and/or the cytosolic transcription factor interferon regulatory factor-3 (IRF-3). Both pathways lead to NF-κB activation, increased gene transcription, and early release of inflammatory factors such as beta interferon by the innate immune system. In a similar way, TLR2 is able to activate the small GTPases Rac-1 and Rac-2, involved in cytoskeletal rearrangement and the generation of motile strength and contraction for movement, phagocytosis, degranulation, and NADPH oxidase activation.

Citation: Kuijpers T, Roos D. 2004. Neutrophils: the Power Within, p 45-70. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch3
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Image of FIGURE 4

FcγRs, polymorphic variants, and associated signaling molecules.The allelic frequencies among the FcγRs behave as susceptibility markers between certain patient groups and control cohorts, or as disease-modifying markers within certain patient cohorts with respect to the symptoms or course of the disease. In the macrophage-specific FcγRIa, no allelic variation has until now been described. In FcγRIIa and FcγIIIa, several allelic variations have been defined.The FcγRIIa-131R/R genotype is associated with a higher binding capacity and affinity for IgG2 by all phagocytes and NK cells, in contrast to its opposite, the homozygous FcγRIIa-131H/H genotype.The inhibitory FcγRIIb contains a polymorphic site in the transmembrane domain. Questions regarding the physiological meaning and functional impact of this polymorphism remain to be answered. The FcγRIIIa-176V/F genotype variation adds considerable complexity to disease outcome and interpretation. These latter two receptors are expressed on macrophages and NK cells. The neutrophil-specific antigens NA1 and NA2 are located on lipid-anchored FcγRIIIb. NA1 and NA2 forms of FcγRIIIb differ by four amino acids and the corresponding genes by five nucleotides.A direct functional consequence has not been firmly established.Variations in all these FcγR polymorphic gene frequencies are encountered among ethnic groups. Altered forms of these genes may thus create clinical variation in case of IgG-dependent inflammatory and/or infectious disease among the various races, as do the different individual genetic backgrounds.

Citation: Kuijpers T, Roos D. 2004. Neutrophils: the Power Within, p 45-70. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch3
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Image of FIGURE 5

Recognition, uptake, and killing of microorganisms by neutrophils. Opsonized microorganisms bind with Fc regions of IgG antibodies to FcγRs and with C3b/C3bi fragments to CR1 and CR3 on the surface of the neutrophils. As a result, the microorganisms are engulfed by the neutrophils and taken up into an intracellular phagosome. Neutrophil granules fuse with the phagosome membrane and deposit their contents into the phagosome. A membrane-bound oxidase is activated and starts to generate superoxide (O ) also into the phagosome.The superoxide is spontaneously converted into hydrogen peroxide (HO), which reacts with MPO released by the granules to yield additional toxic oxygen compounds. Sensing and triggering through TLRs and other sensing molecules take place at the outer plasma membrane and at the membrane of the phagolysosome.

Citation: Kuijpers T, Roos D. 2004. Neutrophils: the Power Within, p 45-70. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch3
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Image of FIGURE 6

Apoptosome.APAF-1, a key regulator of the mitochondrial apoptosis pathway, contains three functional regions: an N-terminal CARD that can bind to procaspase-9; a CED- 4-like region enabling self-oligomerization; and a regulatory C terminus with so-called WD- 40 repeats masking the CARD and CED-4 region. During apoptosis, cytochrome is released from the mitochondrial intermembranous space and, together with dATP, can relieve the inhibitory action of the WD-40 repeats to enable the oligomerization of APAF-1 and the subsequent recruitment and activation of procaspase-9 in a so-called apoptosome. Catalytically active processed caspase-9 or inactive unprocessed caspase-9 initially binds to the APAF-1 apoptosome and recruits caspase-3 via an interaction between the active-site cysteine (C287) in caspase- 9 and a critical aspartate (D175) in caspase-3. XIAP, an X-linked member of the inhibitor of apoptosis protein family, is normally present in the cytosol but directly interacts with the “active” apoptosome to associate with oligomerized and processed caspase-9 and thus indirectly as well as directly influences the activation of caspase-3. Progression of apoptosis depends on (i) simultaneous release of Smac/DIABLO from the mitochondria into the cytosol, competing XIAP away from its association with processed caspase-9, thereby allowing caspase-9 to activate caspase; and (ii) caspase-3 cleavage of the XIAP-binding linker region (LR), resulting in the progression of inevitable apoptosis through further activating steps and cleavage of intracellular substrates.Inflammasome(s). Generation of IL-1β and IL-18 via cleavage of its proform requires the activity of an interleukin-converting enzyme (ICE), also known as the CARD-containing caspase-1.The precise mechanism involved in the activation of the proinflammatory caspases remains elusive, but the available data suggest that a high-molecular-weight caspase-activating complex comprises caspase-1, caspase-5, apoptosis-signaling complex (ASC or Pycard), and CARD7 (NALP1 or DEFCAP), both PYRIN and CARD domain-containing proteins sharing structural homology with the cytosolic NODs (NOD-1 and -2).This protein platform (inflammasome) in the cytosol of phagocytes is able to induce pro-IL-1β maturation through the proximity-driven cross-activation of inflammatory caspases, induced by inflammatory triggers such as LPS.The p45 precursor form of caspase-1 (which contains four cleavage sites) is activated, leading to formation of protein subunits (p10 and p20) that are flanked by Asp-X bonds. It is most conceivable that the proenzyme is activated autocatalytically. The active site of caspase-1 at Cys-285 can cleave the 31-kDa precursor protein pro-IL-1β at Asp116-Ala117, whereby it creates the 17.5-kDa mature, biologically active cytokine.Among the rapidly expanding families of proteins containing either or both of these domains, the PYRIN as well as the CARD domain can create interactions between different family members. The classical protein called pyrin by itself, and mutated in FMF (see text), may regulate the inflammasome negatively. Thus, the function of these large complexes depends on the ability of additional CARD or PYRIN domain-containing proteins to regulate the degree of activation. The CARD-containing caspase-9 is thought to propagate a death signal by triggering other caspase activation in response to cytochrome -mediated events, such as the additional caspases (caspase-2, -3, -6, -7, -8, and -10), in which caspase-3 is required for the activation of the four other caspases (-2, -6, -8, and -10) in a feedback amplification loop. In contrast, the CARD-containing caspase-1, -4, and -5 fail to be activated under the same conditions and seem restricted to the inflammatory loop of cytokine release and proinflammatory activity.

Citation: Kuijpers T, Roos D. 2004. Neutrophils: the Power Within, p 45-70. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch3
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Neutropenia: quantitative defects, pathomechanism, and inheritance

Citation: Kuijpers T, Roos D. 2004. Neutrophils: the Power Within, p 45-70. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch3

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