Chapter 1 : Neutrophils Forever ...

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Neutrophils constitute the major type of leukocyte in peripheral blood, with counts ranging from 40 to 70% of the leukocytes under normal conditions. 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. Neutrophil granule constituents are traditionally considered as potent antimicrobial peptides and proteolytic enzymes, specific to the neutrophil. These proteins assist in the killing and digestion of microorganisms but are potentially harmful to the host if released inappropriately. Several causes of neutropenia can be diagnosed. In contrast to the more frequently observed neutropenia associated with mutations, the classical form of severe congenital neutropenia (SCN), i.e., Kostmann syndrome, is an autosomal recessive disease. Recently, it was found to be caused by mutations in the gene. Leukocytes are able to recognize concentration differences in a gradient of chemotaxins and to direct their movement toward the source of these agents, i.e., toward the inflammatory site. A defect in chemotaxis by neutrophils with a disturbed GCSFR or gene cannot be easily reconciled with the function of either of these molecules per se. Toll-like receptors (TLRs) ignite the cytokine response that occurs during infection, and to a large extent, shape the whole of the inflammatory response with all its consequences, both beneficial and harmful. The cellular composition and duration of an inflammatory response may differ among the different inflammatory reactions.

Citation: Kuijpers T, van den Berg T, Roos D. 2009. Neutrophils Forever ..., p 3-26. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch1
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Image of FIGURE 1

(A) Electron microscopy picture showing a human neutrophil with multilobular nucleus and rich granular content. (B) Development of mature neutrophils with transcription factors involved in the differentiation and formation of some important surface proteins and granular components.

Citation: Kuijpers T, van den Berg T, Roos D. 2009. Neutrophils Forever ..., p 3-26. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch1
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Image of FIGURE 2

(A) TLR activation through TLR2 and TLR4 demonstrates the distinctive mechanisms that can be used by either of these surface proteins. The role of CD14 is limited to the sensing and cooperative activation of TLR4 (not shown). Moreover, TLR4 can activate the cell through MyD88/Mal/IRAK-4 but also via interferon response factor-3 (IRF3) phosphorylation in a TRAM/TRIF-dependent manner through inducible IKK (IKKɩ) and TANK-binding kinase-1 (TBK1) (see also chapter 10). TLR2 has been suggested to activate small GTPase Rac, but this TLR2-mediated activation pathway remains to be confirmed. Either way, NF-κB activation occurs and is an important step in transcriptional activity and the production of classical proinflammatory proteins. (B) The activation of endosomal TLR3, TLR7, TLR8, and TLR9 are assumed to activate different pathways. This has been indicated by the different signaling cascades. As shown for TLR3, this receptor triggers the TRAM/TRIF pathway to activate NF-κB and the IRF3- and IRF7-mediated gene transcription. In many cells a similar route of cytoplasmic activation via dsRNA is present which depends on retinoic acidi-inducible glycoprotein-I (RIG-I) or its homologous helicase MDA-5 in a mitochondria-dependent manner. In human neutrophils, TLR3 is not expressed and hence absent; RIG-I expression has not been described in neutrophils. (C) TLR7, -8, and -9 make use of the classical MyD88, which is able to relay their signals in the absence of Mal (in contrast to the TLR2/1, TLR2/6, and TLR4 shown in A). The localization of TLR7, -8, and -9 in human neutrophils is uncertain. IL-8 synthesis in neutrophils completely depends on IRAK-4. However, the immediate induction of adhesion, degranulation, or priming of the NADPH oxidase activity in neutrophils is independent of IRAK-4.

Citation: Kuijpers T, van den Berg T, Roos D. 2009. Neutrophils Forever ..., p 3-26. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch1
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(A) NOD-like receptor (NLR) proteins comprise a diverse protein family (over 20 in humans), indicating that NLRs have evolved to acquire specificity to various pathogenic microorganisms, thereby controlling host-pathogen interactions. The NLRs form the backbone of inflammasomes, which are assumed to become active through a process of “close proximity.” This means that within these protein complexes of NLRs the associated procaspases cross-activate each other by cleavage into enzymatically active proteases. The NLRs have a series of homologous domains that may interact with each other, such as the caspase recruitment domain (CARD), the nucleotide-binding sequence (NBS), or the leucine-rich repeats (LRRs), which act as the ligand-interacting domains. As indicated here for caspase-1 activity, after the cleavage and activation of procaspase-1, its substrate pro-IL-1β (IL-18 or IL-33) is cleaved into the bioactive IL-1β that is being released by the inflammatory cells. Inhibitory proteins in the cytoplasm such as Pyrin or the CARD-containing proteins INCA, pseudo-ICE, or ICEBERG may prevent the inflammasome from becoming activated. (B) NLR proteins are localized to the cytoplasm and recognize microbial products. Many cells contain different inflammasomes with their own specific ligands that may originate from microbial structures, actively taken up or dissipating from the invading pathogen itself. The inflammasomes identified thus far have been listed with their incriminated microbial agents or pathogen-derived ligands shown at the right. The list is of temporary value because of the rapid evolution of the field of inflammasome research to date.

Citation: Kuijpers T, van den Berg T, Roos D. 2009. Neutrophils Forever ..., p 3-26. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch1
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(A) Many proteins of the innate immune system contain so-called caspaserecruitment domains (CARDs). Through CARD-CARD interactions the activating protein kinase RIP2 can interact with NOD1 and NOD2. In murine myeloid cells, CARD9 binds to Bcl-10. In both murine and human lymphocytes, additional molecules such as the paracaspase-domain-containing MALT1, and members of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins, which coordinate signaling pathways emanating from the plasma membrane. When complexed, these members determine the signaling via the antigen receptors to activate NF-κB. The lymphocyte-specific CARD11 (CARMA1) and proposedly its closest homologues are constitutively oligomerized. This oligomerization of CARD11 via the coiled-coil domains is required for NF-κB activation. IKK triggers Bcl-10 degradation by the ubiquitinproteasome system through specific phosphorylation of Bcl-10, resulting in inactivation through negative feedback of the NF-κB activation pathway. (B) Apart from the NODs, also TLRs and surface receptors containing an ITAM motif themselves or associating with an ITAM-containing adaptor protein, such as the common FcR-associated γ-chain of FcγRIIIa or DAP12, have been demonstrated to signal through various CARD-containing proteins. Whether such activating modules or platforms also operate in human neutrophils is likely but remains to be formally shown.

Citation: Kuijpers T, van den Berg T, Roos D. 2009. Neutrophils Forever ..., p 3-26. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch1
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(A) The gene loci for FcγRI and FcγRII-III are located on different bands of chromosome 1q. FcγRIIs are encoded by three genes, and , which has long been assumed to be a pseudogene. As recently demonstrated most explicitly, approximately 20% of healthy individuals carry an gene without a stop codon in exon 3, which creates an open reading frame that results in the functional expression of an activating FcγRIIc. FcγRIIIs are encoded by two genes, one of which is selectively expressed by the neutrophil, FcγRIIIb carrying the allotype NA1 and/or NA2. (B) The FcγRs can functionally be divided into activating and inhibitory receptors. The activation results from the interaction of FcγRs containing an ITAM. The cytoplasmic ITAM motif consists of two copies of the sequence YxxL. Within this motif, the tyrosines are phosphorylated after receptor cross-linking, and the integrity of these conserved sequences is required for efficient phagocytosis. The ITAM motif is present in the cytoplasmic tail of FcγRIIa and in the γ-chains associated with FcγRI and FcγRIIIa; the ζ-chain associated with FcγRIIIa contains three copies of this motif. The single inhibitory IgG receptor, FcγRIIb, contains a so-called ITIM. All FcγRII and FcγRIII isoforms contain amino acid substitutions that are believed to influence their function, as a consequence of genetic variation, i.e., single nucleotide polymorphisms.

Citation: Kuijpers T, van den Berg T, Roos D. 2009. Neutrophils Forever ..., p 3-26. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch1
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Image of FIGURE 6

The NADPH oxidase complex consists of several proteins that have to assemble into an enzymatically active complex before the generation of superoxide may occur. Cytoplasmic components (the p40/p47/p67- complex) are drawn toward the plasma or phagosomal membrane where the interactions with flavocytochrome are governed by the p47- SH3 domain interacting with a polyproline domain in p22-, and by the direct interaction of Rac proteins with gp91- Then, the NADPH-binding site in gp91- is made accessible for NADPH as a substrate and electron donor from the cytosol to start generating superoxide (O ).

Citation: Kuijpers T, van den Berg T, Roos D. 2009. Neutrophils Forever ..., p 3-26. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch1
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Generic image for table

Neutropenia: quantitative defects, pathomechanism, and inheritance

Citation: Kuijpers T, van den Berg T, Roos D. 2009. Neutrophils Forever ..., p 3-26. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch1
Generic image for table

Neutrophil dysfunction: qualitative defects, pathomechanism, and inheritance

Citation: Kuijpers T, van den Berg T, Roos D. 2009. Neutrophils Forever ..., p 3-26. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch1
Generic image for table

PAMPs observed on various microorganisms

Citation: Kuijpers T, van den Berg T, Roos D. 2009. Neutrophils Forever ..., p 3-26. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch1

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