Chapter 3 : Neutrophils: the Power Within

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Neutrophils: the Power Within, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817671/9781555812911_Chap03-1.gif /docserver/preview/fulltext/10.1128/9781555817671/9781555812911_Chap03-2.gif


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
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


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
Permissions and Reprints Request Permissions
Download as Powerpoint
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
Permissions and Reprints Request Permissions
Download as Powerpoint
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
Permissions and Reprints Request Permissions
Download as Powerpoint
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
Permissions and Reprints Request Permissions
Download as Powerpoint
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
Permissions and Reprints Request Permissions
Download as Powerpoint
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
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Adams, M. J.,, and S. Cory. 1998. The Bcl-2 protein family: arbiters of cell survival. Science 281: 1322 1326.
2. Aganna, E.,, F. Martinon,, P. N. Hawkins,, J. B. Ross,, D. C. Swan,, D. R. Booth,, H. J. Lachmann,, R. Gaudet,, P. Woo,, C. Feighery,, F. E. Cotter,, M. Thome,, G. A. Hitman,, J. Tschopp,, and M. F. McDermott. 2002. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum. 46: 2445 2452.
3. Akira, S.,, K. Takeda,, and T. Kaisho. 2001. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2: 675 680.
4. Ambruso, D. R.,, C. Knall,, A. N. Abell,, J. Panepinto,, A. Kurkchubasche,, G. Thurman,, C. Gonzalez-Aller,, A. Hiester,, M. de Boer,, R. J. Harbeck,, R. Oyer,, G. L. Johnson,, and D. Roos. 2000. Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc. Natl. Acad. Sci. USA 97: 4654 4659.
5. Anderson, K. L.,, K. A. Smith,, H. Perkin,, G. Hermanson,, C. G. Anderson,, D. J. Jolly,, R. A. Maki,, and B. E. Torbett. 1999. PU.1 and the granulocyte- and macrophage colony-stimulating factor receptors play distinct roles in late-stage myeloid cell differentiation. Blood 94: 2310 2318.
6. Arbibe, L.,, J. P. Mira,, N. Teusch,, L. Kline,, M. Guha,, N. Mackman,, P. J. Godowski,, R. J. Ulevitch,, and U. G. Knaus. 2000. Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1- dependent pathway. Nat. Immunol. 1: 533 540.
7. Aurrand-Lions, M.,, C. Johnson-Leger,, and B. Imhof. 2002. The last molecular fortress in leukocyte trans-endothelial migration. Nat. Immunol. 3: 116 118.
8. Barclay, A. N.,, G. J. Wright,, G. Brooke,, and M. H. Brown. 2002. CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol. 23: 285 290.
9. Belaaouaj, A.,, R. McCarthy,, M. Baumann,, Z. Gao,, T. J. Ley,, S. N. Abraham,, and S. D. Shapiro. 1998. Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nat. Med. 4: 615 618.
10. Betsuyaku, T.,, F. Liu,, R. M. Senior,, J. S. Haug,, E. J. Brown,, S. L. Jones,, K. Matsushima,, and D. C. Link. 1999. A functional granulocyte colonystimulating factor receptor is required for normal chemoattractant-induced neutrophil activation. J. Clin. Invest. 103: 825 832.
11. Bokoch, G. M. 1996. Chemoattractant signalling and leukocyte activation. Blood 86: 1649 1660.
12. Bouchon, A.,, F. Facchetti,, M. A. Welgand,, and M. Colonna. 2001. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature 410: 1103 1107.
13. Brach, M. A.,, S. deVos,, H. J. Gruss,, and F. Herrmann. 1992. Prolongation of survival of human polymorphonuclear neutrophils by granulocytemacrophage colony-stimulating factor is caused by inhibition of programmed cell death. Blood 80: 2920 2924.
14. Bruhns, P.,, F. Vely,, O. Malbec,, W. H. Fridman,, E. Vivier,, and M. Daeron. 2000. Insufficient phosphorylation prevents FcγRIIB from recruiting the SH2 domain-containing protein tyrosine phosphatase SHP-1. J. Biol. Chem. 275: 37357 37364.
15. Chamaillard, M.,, M. Hashimoto,, Y. Horie,, J. Masumoto,, S. Qiu,, L. Saab,, Y. Ogura,, A. Kawasaki,, K. Fukase,, S. Kusumoto,, M. A. Valvano,, S. J. Foster,, T.W. Mak,, G. Nunez,, and N. Inohara. 2003. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat. Immunol. 4: 702 707.
16. Dale, D. C.,, R. E. Person,, A. A. Boylard,, A. G. Aprikyan,, C. Bos,, M. A. Bonilla,, L. A. Boxer,, G. Kanourakis,, C. Zeidler,, K. Welte,, K. F. Benson,, and M. Horwitz. 2000. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 96: 2317 2322.
17. Daws, M. R.,, L. L. Lanier,, W. R. Seaman,, and J. C. Ryan. 2001. Cloning and characterization of a novel mouse myeloid DAP12-associated receptor family. Eur. J. Immunol. 31: 783 791.
18. Dodé, C.,, N. Le Du,, L. Cuisset,, F. Letourneur,, J. M. Berthelot,, G. Vaudour,, A. Meyrier,, R. A. Watts,, D. G. Scott,, A. Nicholls,, B. Granel,, C. Frances,, F. Garcier,, P. Edery,, S. Boulinguez,, J. P. Domergues,, M. Delpech,, and G. Grateau. 2002. New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am. J. Hum. Genet. 70: 1498 1506.
19. Dong, F.,, D. C. Dale,, M. A. Bonilla,, M. Freedman,, A. A. Fasth,, H. J. Neijens,, J. Palmblad,, G. L. Briars,, G. Carlsson,, A. J. Veerman,, K. Welte,, B. Lowenberg,, and I. P. Touw. 1997. Mutations in the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia. Leukemia 11: 120 125.
20. Dowds, T. A.,, J. Masumoto,, F. F. Chen,, Y. Ogura,, N. Inohara,, and G. Nunez. 2003. Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product. Biochem. Biophys. Res. Commun. 302: 575 580.
21. Dransfield, I.,, S. C. Stocks,, and C. Haslett. 1995. Regulation of cell adhesion molecule expression and function associated with neutrophil apoptosis. Blood 85: 3264 3273.
22. Feldmann, J.,, A. Prieur,, P. Quartier,, P. Berquin,, E. Cortis,, D. Teillac-Hamel,, A. Fischer,, and G. de Saint Basile. 2002. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am. J. Hum. Genet. 70: 198 203.
23. Fiorentino, L.,, C. Stehlik,, V. Oliveira,, M. E. Ariza,, A. Godzik,, and J. C. Reed. 2002. A novel PAAD-containing protein that modulates NF-kappa B induction by cytokines tumor necrosis factor-alpha and interleukin-1beta. J. Biol. Chem. 277: 35333 35340.
24. Fitzgerald, K. A.,, E. M. Palsson-McDermott,, A. G. Bowie,, C. A. Jefferies,, A. S. Mansell,, G. Brady,, E. Brint,, A. Dunne,, P. Gray,, M.T. Harte,, D. McMurray,, D. E. Smith,, J. E. Sims,, T. A. Bird,, and L. A. O'Neill. 2001. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413: 78 83.
25. French FMF Consortium. 1997. A candidate gene for familial Mediterranean fever. Nat. Genet. 17: 2531.
26. Girardin, S. E.,, I. G. Boneca,, L. A. Carneiro,, A. Antignac,, M. Jehanno,, J. Viala,, K. Tedin,, M. K. Taha,, A. Labigne,, U. Zathringer,, A. J. Coyle,, P. S. DiStefano,, J. Bertin,, P. J. Sansonetti,, and D. J. Philpott. 2003a. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science 300: 1584 1587.
27. Girardin, S. E.,, I. G. Boneca,, J. Viala,, M. Chamaillard,, A. Labigne,, G. Thomas,, D. J. Philpott,, and P. J. Sansonetti. 2003b. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J. Biol. Chem. 278: 8869 8872.
28. Green, D. R.,, and G. Melino. 2001. ICE heats up. Cell Death Differ. 8: 549 550.
29. Gutierrez, O.,, C. Pipaon,, N. Inohara,, A. Fontalba,, Y. Ogura,, F. Prosper,, G. Nunez,, and J. L. Fernandez-Luna. 2002. Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation. J. Biol. Chem. 277: 41701 41705.
30. Harton, J. A.,, M.W. Linhoff,, J. Zhang,, and J. P. Ting. 2002. CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotidebinding, and leucine-rich repeat domains. J. Immunol. 169: 4088 4093.
31. Hengartner, M. O. 2000. The biochemistry of apoptosis. Nature 407: 770 776.
32. Hirschfeld, M.,, Y. Ma,, J. H. Weis,, S. N. Vogel,, and J. J. Weis. 2000. Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2. J. Immunol. 165: 618 622.
33. Hlaing, T.,, R. F. Guo,, K.A. Dilley,, J. M. Loussia,, T. A. Morrish,, M. M. Shi,, C. Vincenz,, and P. A. Ward. 2001. Molecular cloning and characterization of DEFCAP-L and -S, two isoforms of a novel member of the mammalian Ced-4 family of apoptosis proteins. J. Biol. Chem. 276: 9230 9238.
34. Hoffman, H. M.,, J. L. Mueller,, D. H. Broide,, A. A. Wanderer,, and R. D. Kolodner. 2001. Mutation of a new gene encoding a putative pyrinlike protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat. Genet. 29: 301 305.
35. Horng, T.,, G. M. Barton,, and R. Medzhitov. 2001. TIRAP: an adapter molecule in the Toll signaling pathway. Nat. Immunol. 2: 835 841.
36. Hugot, J. P.,, M. Chamaillard,, H. Zouali,, S. Lesage,, J. P. Cezard,, J. Belaiche,, S. Almer,, C. Tysk,, C. A. O'Morain,, M. Gassull,, V. Binder,, Y. Finkel,, A. Cortot,, R. Modigliani,, P. Laurent- Puig,, C. Gower-Rousseau,, J. Macry,, J. F. Colombel,, M. M. Sahbatou,, and G. Thomas. 2001. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411: 599 603.
37. Huizinga, T.W.,, M. de Haas,, M. H. van Oers,, M. Kleijer,, H. Vile,, P. A. van der Wouw,, A. Moulijn,, H. van Weezel,, D. Roos,, and A. E. von dem Borne. 1994. The plasma concentration of soluble Fcgamma RIII is related to production of neutrophils. Br. J. Haematol. 87: 459 463.
38. Ingalls, R. R.,, H. Heine,, E. Lien,, A. Yoshimura,, and D. Golenbock. 1999. Lipopolysaccharide recognition, CD14, and lipopolysaccharide receptors. Infect. Dis. Clin. North Am. 13: 341 353.
39. Inohara, N.,, T. Koseki,, L. del Peso,, Y. Hu,, C. Yee,, S. Chen,, R. Carrio,, J. Merino,, D. Liu,, J. Ni,, and G. Nunez. 1999. Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor kB. J. Biol. Chem. 274: 14560 14567.
40. Inohara, N.,, Y. Ogura,, A. Fontalba,, O. Gutierrez,, F. Pons,, J. Crespo,, K. Fukase,, S. Inamura,, S. Kusumoto,, M. Hashimoto,, S. J. Foster,, A. P. Moran,, J. L. Fernandez-Luna,, and G. Nunez. 2003. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J. Biol. Chem. 278: 5509 5512.
41. International FMF Consortium. 1997. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90: 797807.
42. Kasper, B.,, N. Tidow,, D. Grothues,, and K. Welte. 2000. Differential expression and regulation of GTPases (RhoA and Rac2) and GDIs (LyGDI and RhoGDI) in neutrophils from patients with severe congenital neutropenia. Blood 95: 2947 2953.
43. Kawai, T.,, O. Adachi,, T. Ogawa,, K. Takeda,, and S. Akira. 1999. Unresponsiveness of MyD88 deficient mice to endotoxin. Immunity 11: 115 122.
44. Kobayashi, K.,, L. D. Hernandez,, J. E. Galan,, C. A. Janeway, Jr.,, R. Medzhitov,, and R. A. Flavell. 2002. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110: 191 202.
45. Kuijpers, T.W. 2002. Clinical symptoms and neutropenia: the balance of neutrophil development, functional activity, and cell death. Eur. J. Pediatr. 161: S75 S82.
46. Kuijpers, T.W.,, B. C. Hakkert,, M. H. Hart,, and D. Roos. 1992. Neutrophil migration across monolayers of cytokine-prestimulated endothelial cells: a role for platelet-activating factor and IL-8. J. Cell Biol. 117: 565 572.
47. Kuijpers, T.W.,, N. A. Maianski,, A.T. Tool,, G. P. Smit,, J. P. Rake,, D. Roos,, and G. Visser. 2003. The presence of apoptotic neutrophils in the circulation of patients with Glycogen Storage Disease type 1b (GSD1b). Blood 101: 5021 5024.
48. Kurt-Jones, E. A.,, L. Mandell,, C. Whitney,, A. Padgett,, K. Gosselin,, P. E. Newburger,, and R.W. Finberg. 2002. Role of toll-like receptor 2 (TLR2) in neutrophil activation: GM-CSF enhances TLR2 expression and TLR2-mediated interleukin 8 responses in neutrophils. Blood 100: 1860 1868.
49. Kyogoku, C.,, H. M. Dijstelbloem,, N. Tsuchiya,, Y. Hatta,, H. Kato,, A. Yamaguchi,, T. Fukazawa,, M.D. Jansen,, H. Hashimoto,, J. G. van de Winkel,, C. G. Kallenberg,, and K. Tokunaga. 2002. Fcgamma receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility. Arthritis Rheum. 46: 1242 1254.
50. Lekstrom-Himes, J. A.,, S. E. Dorman,, P. Kopar,, S. M. Holland,, and J. I. Gallin. 1999. Neutrophilspecific granule deficiency results from a novel mutation with loss of function of the transcription factor CCAAT/enhancer binding protein epsilon. J. Exp. Med. 189: 1847 1852.
51. Liu, F.,, H. F. Wu,, R. Wesselschmidt,, T. Kornaga,, and D. C. Link. 1996. Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. Immunity 5: 491 501.
52. Liu, Y.,, H. J. Buhring,, K. Zen,, S. L. Burts,, F. J. Schnell,, I. R. Williams,, and C. A. Parkos. 2002. Signal regulatory protein (SIRPα), a cellular ligand for CD47, regulates neutrophil transmigration. J. Biol. Chem. 277: 10028 10036.
53. Loike, J.D.,, L. Cao,, S. Budhu,, E. E. Marcantonio,, J. El Khoury,, S. Hoffman,, T. A. Yednock,, and S. C. Silverstein. 1999. Differential regulation of beta 1 integrins by chemoattractants regulates neutrophil migration through fibrin. J. Cell Biol. 144: 1047 1056.
54. Maianski, N. A.,, F. P. Mul,, J. D. van Buul,, D. Roos,, and T. W. Kuijpers. 2002. Granulocyte Colony-Stimulating factor (G-CSF) inhibits in neutrophils the mitochondria-dependent activation of Caspase-3. Blood 99: 672 679.
55. Malech, H. L.,, and W. M. Nauseef. 1997. Primary inherited defects in neutrophil function: etiology and treatment. Semin. Hematol. 34: 279 290.
56. Martinon, F.,, K. Burns,, and J. Tschopp. 2002. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proILbeta. Mol. Cell 10: 417 426.
57. Miceli-Richard, C.,, S. Lesage,, M. Rybojad,, A. M. Prieur,, S. Manouvrier-Hanu,, R. Hafner,, M. Chamaillard,, H. Zouali,, G. Thomas,, and J. P. Hugot. 2001. CARD15 mutations in Blau syndrome. Nat. Genet. 29: 19 20.
58. Moulding, D. A.,, J. A. Quayle,, C. A. Hart,, and S. W. Edwards. 1998. Mcl-1 expression in human neutrophils: regulation by cytokines and correlation with cell survival. Blood 92: 2495 2502.
59. Murdoch, C.,, and A. Finn. 2000. Chemokine receptors and their role in inflammation and infectious diseases. Blood 95: 3032 3043.
60. Nagase, H.,, M. Miyamasu,, M. Yamaguchi,, M. Imanishi,, N. H. Tsuno,, K. Matsushima,, K. Yamamoto,, Y. Morita,, and K. Hirai. 2002. Cytokine-mediated regulation of CXCR4 expression in human neutrophils. J. Leukoc. Biol. 71: 711 717.
61. Netea, M. G.,, M. van Deuren,, B. J. Kullberg,, J. M. Cavaillon,, and J.W. van der Meer. 2002. Does the shape of lipid A determine the interaction of LPS with Toll-like receptors? Trends Immunol. 23: 135 139.
62. Ogden, C.A.,, A. deCathelineau,, P. R. Hoffmann,, D. Bratton,, B. Ghebrehiwet,, V. A. Fadok,, and P. M. Henson. 2001. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J. Exp. Med. 194: 781 795.
63. Ogura, Y.,, D. K. Bonen,, N. Inohara,, D. L. Nicolae,, F. F. Chen,, R. Ramos,, H. Britton,, T. Moran,, R. Karaliuskas,, R. H. Duerr,, J. P. Achkar,, S. R. Brant,, T. M. Bayless,, B. S. Kirschner,, S. B. Hanauer,, G. Nunez,, and J. H. Cho. 2001a. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411: 603 606.
64. Ogura, Y.,, N. Inohara,, A. Benito,, F. F. Chen,, S. Yamaoka,, and G. Nunez. 2001b. Nod2, a Nod1/ Apaf-1 family member that is restricted to monocytes and activates NF-kB. J. Biol. Chem. 276: 4812 4818.
65. Oldenborg, P. A.,, A. Zheleznyak,, Y. F. Fang,, C. F. Lagenaur,, H. D. Gresham,, and F. P. Lindberg. 2000. Role of CD47 as a marker of self on red blood cells. Science 288: 2051 2054.
66. Ozinsky, A.,, D. M. Underhill,, J. D. Fontenot,, A. M. Hajjar,, K. D. Smith,, C. B. Wilson,, L. Schroeder,, and A. Aderem. 2000. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc. Natl. Acad. Sci. USA 97: 13766 13771.
67. Pearse, R. N.,, T. Kawabe,, S. Bolland,, R. Guinamard,, T. Kurosaki,, and J.V. Ravetch. 1999. SHIP recruitment attenuates Fc gamma RIIBinduced B cell apoptosis. Immunity 10: 753 760.
68. Poltorak, A.,, X. He,, I. Smirnova,, M. Y. Liu,, C. V. Huffel,, X. Du,, D. Birdwell,, E. Alejos,, M. Silva,, C. Galanos,, M. Freudenberg,, P. Ricciardi- Castagnol,, B. Layton,, and B. Beutler. 1998. Defective LPS signaling in C3H/HeJ and C57BL/ 10ScCr mice: mutations in Tlr4 gene. Science 282: 2085 2088.
69. Ravetch, J.V.,, and S. Bolland. 2001. IgG Fc receptors. Annu. Rev. Immunol. 19: 275 290.
70. Ravetch, J. V.,, and L. L. Lanier. 2000. Immune inhibitory receptors. Science 290: 84 89.
71. Reeves, E. P.,, H. Lu,, H. L. Jacobs,, C. G. Messina,, S. Bolsover,, G. Gabella,, E. O. Potma,, A. Warley,, J. Roes,, and A.W. Segal. 2002. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 416: 291 297.
72. Roos, D.,, and J.T. Curnutte,. 1999. Chronic granulomatous disease, p. 353 374. In H. D. Ochs,, C. I. E. Smith,, and J. M. Puck (ed.), Primary Immunodeficiency Diseases. A Molecular and Genetic Approach. Oxford University Press, New York, N.Y.
73. Sabroe, I.,, E. C. Jones,, L. R. Usher,, M. K. Whyte,, and S. K. Dower. 2002. Toll-like receptor (TLR)2 and TLR4 in human peripheral blood granulocytes: a critical role for monocytes in leukocyte lipopolysaccharide responses. J. Immunol. 168: 4701 4710.
74. Savill, J.,, and V. Fadok. 2000. Corpse clearance defines the meaning of cell death. Nature 407: 784 788.
75. Shimazu, R.,, S. Akashi,, H. Ogata,, Y. Nagai,, K. Fukudome,, K. Miyake,, and M. Kimoto. 1999. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med. 189: 1777 1782.
76. Shiohara, M.,, S. Taniguchi,, J. Masumoto,, K. Yasui,, K. Koike,, A. Komiyama,, and J. Sagara. 2002. ASC, which is composed of a PYD and a CARD, is up-regulated by inflammation and apoptosis in human neutrophils. Biochem. Biophys. Res. Commun. 293: 1314 1318.
77. Springer, T. A. 1994. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76: 301 314.
78. Suzuki, N.,, S. Suzuki,, G. S. Duncan,, D. G. Millar,, T. Wada,, C. Mirtsos,, H. Takada,, A. Wakeham,, A. Itie,, S. Li,, J. M. Penninger,, H. Wesche,, P. S. Ohashi,, T. W. Mak,, and W. C. Yeh. 2002. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 416: 750 756.
79. Thornberry, N. A.,, and Y. Lazebnik. 1998. Caspases: enemies within. Science 281: 1312 1316.
80. Van den Berg, J. M.,, S. Weyer,, J. J. Weening,, D. Roos,, and T.W. Kuijpers. 2001. Divergent effects of tumor necrosis factor alpha on apoptosis of human neutrophils. J. Leukoc. Biol. 69: 467 473.
81. Visintin, A.,, A. Mazzoni,, J. H. Spitzer,, D. H. Wyllie,, S. K. Dower,, and D. M. Segal. 2001. Regulation of toll-like receptors in human monocytes and dendritic cells. J. Immunol. 166: 249 255.
82. Wang, L.,, G. A. Manji,, J. M. Grenier,, A. Al- Garawi,, S. Merriam,, J. M. Lora,, B. J. Geddes,, M. Briskin,, P. S. DiStefano,, and J. Bertin. 2002. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase- 1-dependent cytokine processing. J. Biol. Chem. 277: 29874 29880.
83. Weiss, S. J. 1989. Tissue destruction by neutrophils. N. Engl. J. Med. 320: 365 376.
84. Young, N.T.,, and M. Uhrberg. 2002. KIR expression shapes cytotoxic repertoires: a developmental program of survival. Trends Immunol. 23: 71 75.
85. Zeidler, C.,, L. A. Boxer,, D. C. Dale,, M. Freedman,, S. Kinsey,, and K. Welte. 2000. Management of Kostmann syndrome in the G-CSF era. Br. J. Hematol. 109: 490 495.
86. Zhang, P.,, A. Iwama,, M. W. Datta,, G. J. Darlington,, D. C. Link,, and D. G. Tenen. 1998. Upregulation of interleukin 6 and granulocyte colony-stimulating factor receptors by transcription factor CCAAT enhancer binding protein alpha (C/EBP alpha) is critical for granulopoiesis. J. Exp. Med. 188: 1173 1184.


Generic image for table

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

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error