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Neutrophil migration in infection and wound repair: going forward in reverse

Key Points

  • Complementary models have been developed to study neutrophil migration, including microfluidics and live imaging using mice and zebrafish.

  • Neutrophil migration in response to injury or infection occurs in phases: early recruitment, amplification and resolution.

  • Early-recruited neutrophils modulate the amplification phase both directly and indirectly through the activation of tissue and tissue-resident cells, producing sustained signals such as the CXC-chemokine ligand 8 family chemokines.

  • Activated neutrophils at a site of inflammation do not necessarily undergo apoptosis but in some circumstances might undergo reverse migration away from the site of damage (reverse neutrophil migration) and/or re-enter the circulation (reverse transendothelial migration (rTEM)).

  • Neutrophil forward and reverse migration may be attractive targets for anti-inflammatory therapies.

Abstract

Neutrophil migration and its role during inflammation has been the focus of increased interest in the past decade. Advances in live imaging and the use of new model systems have helped to uncover the behaviour of neutrophils in injured and infected tissues. Although neutrophils were considered to be short-lived effector cells that undergo apoptosis in damaged tissues, recent evidence suggests that neutrophil behaviour is more complex and, in some settings, neutrophils might leave sites of tissue injury and migrate back into the vasculature. The role of reverse migration and its contribution to resolution of inflammation remains unclear. In this Review, we discuss the different cues within tissues that mediate neutrophil forward and reverse migration in response to injury or infection and the implications of these mechanisms to human disease.

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Figure 1: The phases of neutrophil recruitment.
Figure 2: Mechanisms that may be involved in neutrophil reverse migration.

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References

  1. Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Nathan, C. Neutrophils and immunity: challenges and opportunities. Nat. Rev. Immunol. 6, 173–182 (2006).

    CAS  PubMed  Google Scholar 

  3. Borregaard, N. Neutrophils, from marrow to microbes. Immunity 33, 657–670 (2010).

    CAS  PubMed  Google Scholar 

  4. Caielli, S., Banchereau, J. & Pascual, V. Neutrophils come of age in chronic inflammation. Curr. Opin. Immunol. 24, 671–677 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Ley, K. Integration of inflammatory signals by rolling neutrophils. Immunol. Rev. 186, 8–18 (2002).

    CAS  PubMed  Google Scholar 

  6. Gambardella, L. & Vermeren, S. Molecular players in neutrophil chemotaxis—focus on PI3K and small GTPases. J. Leukoc. Biol. 94, 603–612 (2013).

    CAS  PubMed  Google Scholar 

  7. Ng, L. G. et al. Visualizing the neutrophil response to sterile tissue injury in mouse dermis reveals a three-phase cascade of events. J. Investigative Dermatol. 131, 2058–2068 (2011).

    CAS  Google Scholar 

  8. Lämmermann, T. In the eye of the neutrophil swarm-navigation signals that bring neutrophils together in inflamed and infected tissues. J. Leukoc. Biol. pii: jlb.1MR0915-403 (2015).

  9. Nourshargh, S. & Alon, R. Leukocyte migration into inflamed tissues. Immunity 41, 694–707 (2014).

    CAS  PubMed  Google Scholar 

  10. Weninger, W., Biro, M. & Jain, R. Leukocyte migration in the interstitial space of non-lymphoid organs. Nat. Rev. Immunol. 14, 232–246 (2014).

    CAS  PubMed  Google Scholar 

  11. Futosi, K., Fodor, S. & Mócsai, A. Neutrophil cell surface receptors and their intracellular signal transduction pathways. Int. Immunopharmacol. 17, 638–650 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Sun, L. & Ye, R. D. Role of G protein-coupled receptors in inflammation. Acta Pharmacol. Sin. 33, 342–350 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Viola, A. & Luster, A. D. Chemokines and their receptors: drug targets in immunity and inflammation. Annu. Rev. Pharmacol. Toxicol. 48, 171–197 (2008).

    CAS  PubMed  Google Scholar 

  14. Pittman, K. & Kubes, P. Damage-associated molecular patterns control neutrophil recruitment. J. Innate Immun. 5, 315–323 (2013).

    CAS  PubMed  Google Scholar 

  15. Broggi, A. & Granucci, F. Microbe- and danger-induced inflammation. Mol. Immunol. 63, 127–133 (2015).

    CAS  PubMed  Google Scholar 

  16. Vénéreau, E., Ceriotti, C. & Bianchi, M. E. DAMPs from Cell Death to New Life. Frontiers Immunol. 6, 422 (2015).

    Google Scholar 

  17. Cordeiro, J. V. V. & Jacinto, A. The role of transcription-independent damage signals in the initiation of epithelial wound healing. Nat. Rev. Mol. Cell Biol. 14, 249–262 (2013).

    CAS  PubMed  Google Scholar 

  18. Niethammer, P., Grabher, C., Look, A. T. & Mitchison, T. J. A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature 459, 996–999 (2009). This is the first paper to visualize H 2 O 2 tissue gradients in wound-induced inflammatory responses using zebrafish.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Moreira, S., Stramer, B., Evans, I., Wood, W. & Martin, P. Prioritization of competing damage and developmental signals by migrating macrophages in the Drosophila embryo. Curr. Biol. 20, 464–470 (2010).

    CAS  PubMed  Google Scholar 

  20. Yoo, S. K., Starnes, T. W., Deng, Q. & Huttenlocher, A. Lyn is a redox sensor that mediates leukocyte wound attraction in vivo. Nature 480, 109–112 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Klyubin, I. V., Kirpichnikova, K. M. & Gamaley, I. A. Hydrogen peroxide-induced chemotaxis of mouse peritoneal neutrophils. Eur. J. Cell Biol. 70, 347–351 (1996).

    CAS  PubMed  Google Scholar 

  22. Kovács, M. et al. The Src family kinases Hck, Fgr, and Lyn are critical for the generation of the in vivo inflammatory environment without a direct role in leukocyte recruitment. J. Exp. Med. 211, 1993–2011 (2014).

    PubMed  PubMed Central  Google Scholar 

  23. Baroja-Mazo, A., Barberà- Cremades, M. & Pelegrín, P. The participation of plasma membrane hemichannels to purinergic signaling. Biochim. Biophys. Acta 1828, 79–93 (2013).

    CAS  PubMed  Google Scholar 

  24. de Oliveira, S. et al. ATP modulates acute inflammation in vivo through dual oxidase 1-derived H2O2 production and NF-κB activation. J. Immunol. 192, 5710–5719 (2014).

    CAS  PubMed  Google Scholar 

  25. Elliott, M. R. et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282–286 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen, Y. et al. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314, 1792–1795 (2006).

    CAS  PubMed  Google Scholar 

  27. Bao, Y. et al. mTOR and differential activation of mitochondria orchestrate neutrophil chemotaxis. J. Cell Biol. 210, 1153–1164 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kukulski, F. et al. Extracellular ATP and P2 receptors are required for IL-8 to induce neutrophil migration. Cytokine 46, 166–170 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Lecut, C. et al. P2X1 ion channels promote neutrophil chemotaxis through Rho kinase activation. J. Immunol. 183, 2801–2809 (2009).

    CAS  PubMed  Google Scholar 

  30. Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Raoof, M., Zhang, Q., Itagaki, K. & Hauser, C. J. Mitochondrial peptides are potent immune activators that activate human neutrophils via FPR-1. J. Trauma 68, 1328 (2010).

    CAS  PubMed  Google Scholar 

  32. Li, L. et al. New development in studies of formyl-peptide receptors: critical roles in host defense. J. Leukoc. Biol. 99, 425–435 (2015).

    PubMed  PubMed Central  Google Scholar 

  33. McDonald, B. et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330, 362–366 (2010).

    CAS  PubMed  Google Scholar 

  34. Pase, L. et al. Neutrophil-delivered myeloperoxidase dampens the hydrogen peroxide burst after tissue wounding in zebrafish. Curr. Biol. 22, 1818–1824 (2012).

    CAS  PubMed  Google Scholar 

  35. Russo, R. C., Garcia, C. C., Teixeira, M. M. & Amaral, F. A. The CXCL8/IL-8 chemokine family and its receptors in inflammatory diseases. Expert Rev. Clin. Immunol. 10, 593–619 (2014).

    CAS  PubMed  Google Scholar 

  36. Kobayashi, Y. The role of chemokines in neutrophil biology. Frontiers Biosci. 13, 2400–2407 (2008).

    CAS  Google Scholar 

  37. Sai, J., Raman, D., Liu, Y., Wikswo, J. & Richmond, A. Parallel phosphatidylinositol 3-kinase (PI3K)-dependent and Src-dependent pathways lead to CXCL8-mediated Rac2 activation and chemotaxis. J. Biol. Chem. 283, 26538–26547 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Neel, N. F. et al. VASP is a CXCR2-interacting protein that regulates CXCR2-mediated polarization and chemotaxis. J. Cell Sci. 122, 1882–1894 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Lindley, I. et al. Synthesis and expression in Escherichia coli of the gene encoding monocyte-derived neutrophil-activating factor: biological equivalence between natural and recombinant neutrophil-activating factor. Proc. Natl Acad. Sci. USA 85, 9199–9203 (1988).

    CAS  PubMed  Google Scholar 

  40. de Oliveira, S. et al. Cxcl8 (IL-8) mediates neutrophil recruitment and behavior in the zebrafish inflammatory response. J. Immunol. 190, 4349–4359 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Deng, Q. et al. Localized bacterial infection induces systemic activation of neutrophils through Cxcr2 signaling in zebrafish. J. Leukoc. Biol. 93, 761–769 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Sarris, M. et al. Inflammatory chemokines direct and restrict leukocyte migration within live tissues as glycan-bound gradients. Curr. Biol. 22, 2375–2382 (2012). This work identified glycan-bound CXCL8 gradients in vivo that mediate neutrophil directed migration to inflamed tissue in zebrafish.

    CAS  PubMed  Google Scholar 

  43. Cacalano, G. et al. Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog. Science 265, 682–684 (1994).

    CAS  PubMed  Google Scholar 

  44. Devalaraja, R. M. et al. Delayed wound healing in CXCR2 knockout mice. J. Invest. Dermatol. 115, 234–244 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Monneau, Y., Arenzana-Seisdedos, F. & Lortat-Jacob, H. The sweet spot: how GAGs help chemokines guide migrating cells. J. Leukoc. Biol. pii: jlb.3MR0915-440R (2015).

  46. Middleton, J. et al. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91, 385–395 (1997).

    CAS  PubMed  Google Scholar 

  47. Powell, W. S., Gravel, S., MacLeod, R. J., Mills, E. & Hashefi, M. Stimulation of human neutrophils by 5-oxo-6,8,11,14-eicosatetraenoic acid by a mechanism independent of the leukotriene B4 receptor. J. Biol. Chem. 268, 9280–9286 (1993).

    CAS  PubMed  Google Scholar 

  48. Øynebråten, I. et al. Characterization of a novel chemokine-containing storage granule in endothelial cells: evidence for preferential exocytosis mediated by protein kinase A and diacylglycerol. J. Immunol. 175, 5358–5369 (2005).

    PubMed  Google Scholar 

  49. Hol, J., Wilhelmsen, L. & Haraldsen, G. The murine IL-8 homologues KC, MIP-2, and LIX are found in endothelial cytoplasmic granules but not in Weibel-Palade bodies. J. Leukoc. Biol. 87, 501–508 (2010).

    CAS  PubMed  Google Scholar 

  50. Iyer, S. S. et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc. Natl Acad. Sci. USA 106, 20388–20393 (2009).

    CAS  PubMed  Google Scholar 

  51. Enyedi, B., Kala, S., Nikolich-Zugich, T. & Niethammer, P. Tissue damage detection by osmotic surveillance. Nat. Cell Biol. 15, 1123–1130 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Sadik, C. D. & Luster, A. D. Lipid-cytokine-chemokine cascades orchestrate leukocyte recruitment in inflammation. J. Leukoc. Biol. 91, 207–215 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Afonso, P. V. et al. LTB4 is a signal-relay molecule during neutrophil chemotaxis. Dev. Cell 22, 1079–1091 (2012). This study describes the role of autocrine LTB 4 gradients at the leading edge that guide neutrophil recruitment to sites of inflammation.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Lämmermann, T. et al. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498, 371–375 (2013). This work reports an initial molecular map of different factors that modulate neutrophil swarming behaviour in response to tissue damage in mice.

    PubMed  Google Scholar 

  55. Wipke, B. T. & Allen, P. M. Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. J. Immunol. 167, 1601–1608 (2001).

    CAS  PubMed  Google Scholar 

  56. Chen, M. et al. Neutrophil-derived leukotriene B4 is required for inflammatory arthritis. J. Exp. Med. 203, 837–842 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Hazeldine, J., Hampson, P., Opoku, F. A., Foster, M. & Lord, J. M. N-Formyl peptides drive mitochondrial damage associated molecular pattern induced neutrophil activation through ERK1/2 and P38 MAP kinase signalling pathways. Injury 46, 975–984 (2015).

    PubMed  Google Scholar 

  58. Chou, R. C. et al. Lipid-cytokine-chemokine cascade drives neutrophil recruitment in a murine model of inflammatory arthritis. Immunity 33, 266–278 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Van den Steen, P. E., Proost, P., Wuyts, A., Van Damme, J. & Opdenakker, G. Neutrophil gelatinase B potentiates interleukin-8 tenfold by amino-terminal processing, whereas it degrades CTAP-III, PF-4, and GRO-α and leaves RANTES and MCP-2 intact. Blood 96, 2673–2681 (2000).

    CAS  PubMed  Google Scholar 

  60. Tester, A. M. et al. LPS responsiveness and neutrophil chemotaxis in vivo require PMN MMP-8 activity. PLoS ONE 2, e312. (2007).

    PubMed  PubMed Central  Google Scholar 

  61. Afonso, P. V., McCann, C. P., Kapnick, S. M. & Parent, C. A. Discoidin domain receptor 2 regulates neutrophil chemotaxis in 3D collagen matrices. Blood 121, 1644–1650 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Soehnlein, O. & Lindbom, L. Phagocyte partnership during the onset and resolution of inflammation. Nat. Rev. Immunol. 10, 427–439 (2010).

    CAS  PubMed  Google Scholar 

  63. Peters, N. C. et al. In vivo imaging reveals an essential role for neutrophils in leishmaniasis transmitted by sand flies. Science 321, 970–974 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Kreisel, D. et al. In vivo two-photon imaging reveals monocyte-dependent neutrophil extravasation during pulmonary inflammation. Proc. Natl Acad. Sci. USA 107, 18073–18078 (2010).

    CAS  PubMed  Google Scholar 

  65. Chtanova, T. et al. Dynamics of neutrophil migration in lymph nodes during infection. Immunity 29, 487–496 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Silva, M. T. Bacteria-induced phagocyte secondary necrosis as a pathogenicity mechanism. J. Leukoc. Biol. 88, 885–896 (2010).

    CAS  PubMed  Google Scholar 

  67. Gonzalez, C. D., Ledo, C., Giai, C., Garófalo, A. & Gómez, M. I. The Sbi protein contributes to Staphylococcus aureus inflammatory response during systemic infection. PLoS ONE 10, e0131879 (2015).

    PubMed  PubMed Central  Google Scholar 

  68. Abtin, A. et al. Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection. Nat. Immunol. 15, 45–53 (2014).

    CAS  PubMed  Google Scholar 

  69. Spinner, J. L., Hasenkrug, A. M., Shannon, J. G., Kobayashi, S. D. & Hinnebusch, B. J. Role of the Yersinia YopJ protein in suppressing interleukin-8 secretion by human polymorphonuclear leukocytes. Microbes Infect. 18, 21–29 (2016).

    CAS  PubMed  Google Scholar 

  70. Palm, N. W. & Medzhitov, R. Pattern recognition receptors and control of adaptive immunity. Immunol. Rev. 227, 221–233 (2009).

    CAS  PubMed  Google Scholar 

  71. Schiwon, M. et al. Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium. Cell 156, 456–468 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Sacramento, L. et al. TLR9 signaling on dendritic cells regulates neutrophil recruitment to inflammatory foci following Leishmania infantum infection. Infect. Immun. 83, 4604–4616 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Abraham, S. N. & John, A. L. Mast cell-orchestrated immunity to pathogens. Nat. Rev. Immunol. 10, 440–452 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Krishna, S. & Miller, L. S. Innate and adaptive immune responses against Staphylococcus aureus skin infections. Semin. Immunopathol. 34, 261–280 (2012).

    CAS  PubMed  Google Scholar 

  75. Malaviya, R., Ikeda, T., Ross, E. & Abraham, S. N. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-α. Nature 381, 77–80 (1996).

    CAS  PubMed  Google Scholar 

  76. Huang, C. et al. Induction of a selective and persistent extravasation of neutrophils into the peritoneal cavity by tryptase mouse mast cell protease 6. J. Immunol. 160, 1910–1919 (1998).

    CAS  PubMed  Google Scholar 

  77. Malaviya, R. & Abraham, S. N. Role of mast cell leukotrienes in neutrophil recruitment and bacterial clearance in infectious peritonitis. J. Leukoc. Biol. 67, 841–846 (2000).

    CAS  PubMed  Google Scholar 

  78. Miller, L. S. et al. Inflammasome-mediated production of IL-1β is required for neutrophil recruitment against Staphylococcus aureus in vivo. J. Immunol. 179, 6933–6942 (2007).

    CAS  PubMed  Google Scholar 

  79. Shimada, T. et al. Staphylococcus aureus evades lysozyme-based peptidoglycan digestion that links phagocytosis, inflammasome activation, and IL-1β secretion. Cell Host Microbe 7, 38–49 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Miller, L. S. et al. MyD88 mediates neutrophil recruitment initiated by IL-1R but not TLR2 activation in immunity against Staphylococcus aureus. Immunity 24, 79–91 (2006).

    CAS  PubMed  Google Scholar 

  81. Sun, K., Salmon, S. L., Lotz, S. A. & Metzger, D. W. Interleukin-12 promotes γ interferon-dependent neutrophil recruitment in the lung and improves protection against respiratory Streptococcus pneumoniae infection. Infect. Immun. 75, 1196–1202 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kabir, S. The role of interleukin-17 in the Helicobacter pylori induced infection and immunity. Helicobacter 16, 1–8 (2011).

    CAS  PubMed  Google Scholar 

  83. Scapini, P. & Cassatella, M. A. Social networking of human neutrophils within the immune system. Blood 124, 710–719 (2014).

    CAS  PubMed  Google Scholar 

  84. Isailovic, N., Daigo, K., Mantovani, A. & Selmi, C. Interleukin-17 and innate immunity in infections and chronic inflammation. J. Autoimmun 60, 1–11 (2015).

    CAS  PubMed  Google Scholar 

  85. Rendon, J. L. & Choudhry, M. A. Th17 cells: critical mediators of host responses to burn injury and sepsis. J. Leukoc. Biol. 92, 529–538 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Mölne, L., Verdrengh, M. & Tarkowski, A. Role of neutrophil leukocytes in cutaneous infection caused by Staphylococcus aureus. Infect. Immun. 68, 6162–6167 (2000).

    PubMed  PubMed Central  Google Scholar 

  87. Ley, K., Smith, E. & Stark, M. A. IL-17A-producing neutrophil-regulatory Tn lymphocytes. Immunol. Res. 34, 229–242 (2006).

    CAS  PubMed  Google Scholar 

  88. Xu, S. & Cao, X. Interleukin-17 and its expanding biological functions. Cell. Mol. Immunol. 7, 164–174 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Cho, J. S. et al. IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J. Clin. Invest. 120, 1762–1773 (2010).

    PubMed  PubMed Central  Google Scholar 

  90. Liese, J., Rooijakkers, S. H., van Strijp, J. A., Novick, R. P. & Dustin, M. L. Intravital two-photon microscopy of host-pathogen interactions in a mouse model of Staphylococcus aureus skin abscess formation. Cell. Microbiol. 15, 891–909 (2013).

    CAS  PubMed  Google Scholar 

  91. Tan, R. S., Ho, B., Leung, B. P. & Ding, J. L. TLR cross-talk confers specificity to innate immunity. Int. Rev. Immunol. 33, 443–453 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Deng, Q., Harvie, E. A. & Huttenlocher, A. Distinct signalling mechanisms mediate neutrophil attraction to bacterial infection and tissue injury. Cell. Microbiol. 14, 517–528 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Yan, B. et al. IL-1β and reactive oxygen species differentially regulate neutrophil directional migration and Basal random motility in a zebrafish injury-induced inflammation model. J. Immunol. 192, 5998–6008 (2014).

    CAS  PubMed  Google Scholar 

  94. Hamza, B. & Irimia, D. Whole blood human neutrophil trafficking in a microfluidic model of infection and inflammation. Lab. Chip 15, 2625–2633 (2015). This work shows that zymosan particles can 'trap' neutrophils and inhibit neutrophil fugetaxis in vitro.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Liu, Y., Chen, G.-Y. Y. & Zheng, P. CD24-Siglec G/10 discriminates danger- from pathogen-associated molecular patterns. Trends Immunol. 30, 557–561 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Chen, G.-Y. Y., Brown, N. K., Zheng, P. & Liu, Y. Siglec-G/10 in self-nonself discrimination of innate and adaptive immunity. Glycobiology 24, 800–806 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Chen, G.-Y. Y., Tang, J., Zheng, P. & Liu, Y. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 323, 1722–1725 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Kruger, P. et al. Neutrophils: Between host defence, immune modulation, and tissue injury. PLoS Pathog. 11, e1004651 (2015).

    PubMed  PubMed Central  Google Scholar 

  99. Buckley, C. D., Gilroy, D. W., Serhan, C. N., Stockinger, B. & Tak, P. P. The resolution of inflammation. Nat. Rev. Immunol. 13, 59–66 (2013).

    CAS  PubMed  Google Scholar 

  100. Hughes, J. et al. Neutrophil fate in experimental glomerular capillary injury in the rat. Emigration exceeds in situ clearance by apoptosis. Am. J. Pathol. 150, 223–234 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Mathias, J. R. et al. Resolution of inflammation by retrograde chemotaxis of neutrophils in transgenic zebrafish. J. Leukoc. Biol. 80, 1281–1288 (2006). This paper is the first time that neutrophil reverse migration was visualized in vivo using zebrafish.

    CAS  PubMed  Google Scholar 

  102. Yoo, S. K. & Huttenlocher, A. Spatiotemporal photolabeling of neutrophil trafficking during inflammation in live zebrafish. J. Leukoc. Biol. 89, 661–667 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Hall, C. et al. Transgenic zebrafish reporter lines reveal conserved Toll-like receptor signaling potential in embryonic myeloid leukocytes and adult immune cell lineages. J. Leukoc. Biol. 85, 751–765 (2009).

    CAS  PubMed  Google Scholar 

  104. Buckley, C. D. et al. Identification of a phenotypically and functionally distinct population of long-lived neutrophils in a model of reverse endothelial migration. J. Leukoc. Biol. 79, 303–311 (2006). This study identifies a subpopulation of human neutrophils that undergo rTEM in vitro . In addition, the authors identify this subpopulation in the human circulation in inflammatory conditions.

    CAS  PubMed  Google Scholar 

  105. Elks, P. M. et al. Activation of hypoxia-inducible factor-1α (Hif-1α) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model. Blood 118, 712–722 (2011).

    CAS  PubMed  Google Scholar 

  106. Ellett, F., Elks, P. M., Robertson, A. L., Ogryzko, N. V. & Renshaw, S. A. Defining the phenotype of neutrophils following reverse migration in zebrafish. J. Leukoc. Biol. 98, 975–981 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Robertson, A. L. et al. A zebrafish compound screen reveals modulation of neutrophil reverse migration as an anti-inflammatory mechanism. Sci. Transl Med. 6, 225ra29 (2014). This work shows how zebrafish can be used for high-throughput drug screens to identify small molecules that modulate neutrophil reverse migration.

    PubMed  PubMed Central  Google Scholar 

  108. Tauzin, S., Starnes, T. W., Becker, F. B., Lam, P.-Y. Y. & Huttenlocher, A. Redox and Src family kinase signaling control leukocyte wound attraction and neutrophil reverse migration. J. Cell Biol. 207, 589–598 (2014). This paper characterizes a macrophage ROS–SFK signalling pathway that mediates neutrophil reverse migration.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Duffy, D. et al. Neutrophils transport antigen from the dermis to the bone marrow, initiating a source of memory CD8+ T cells. Immunity 37, 917–929 (2012). This study shows that neutrophils can transport virus from the dermis to the bone marrow, providing a source of antigen that triggers proliferation of virus-specific memory CD8+ T cells.

    CAS  PubMed  Google Scholar 

  110. Woodfin, A. et al. The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo. Nat. Immunol. 12, 761–769 (2011). This is the first report of rTEM in vivo in an ischaemia–reperfusion mouse model.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Hamza, B. et al. Retrotaxis of human neutrophils during mechanical confinement inside microfluidic channels. Integr. Biol. 6, 175–183 (2014). This study reports that more than 90% of human neutrophils can move persistently against chemoattractant gradients over long distances (retrotaxis) using microfluidic channels.

    CAS  Google Scholar 

  112. Vianello, F., Olszak, I. T. & Poznansky, M. C. Fugetaxis: active movement of leukocytes away from a chemokinetic agent. J. Mol. Med. 83, 752–763 (2005).

    PubMed  Google Scholar 

  113. Starnes, T. W. & Huttenlocher, A. Neutrophil reverse migration becomes transparent with zebrafish. Adv. Hematol. 2012, 398640 (2012).

    PubMed  PubMed Central  Google Scholar 

  114. Tharp, W. G. et al. Neutrophil chemorepulsion in defined interleukin-8 gradients in vitro and in vivo. J. Leukoc. Biol. 79, 539–554 (2006).

    CAS  PubMed  Google Scholar 

  115. Kuijpers, T. & Lutter, R. Inflammation and repeated infections in CGD: two sides of a coin. Cell. Mol. Life Sci. 69, 7–15 (2012).

    CAS  PubMed  Google Scholar 

  116. Serhan, C. N., Chiang, N., Dalli, J. & Levy, B. D. Lipid mediators in the resolution of inflammation. Cold Spring Harb. Perspect. Biol. 7, a016311 (2015).

    PubMed Central  Google Scholar 

  117. Buckley, C. D., Gilroy, D. W. & Serhan, C. N. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity 40, 315–327 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Serhan, C. N. & Chiang, N. Resolution phase lipid mediators of inflammation: agonists of resolution. Curr. Opin. Pharm. 13, 632–640 (2013).

    CAS  Google Scholar 

  119. Colom, B. et al. Leukotriene B4-neutrophil elastase axis drives neutrophil reverse transendothelial cell migration in vivo. Immunity 42, 1075–1086 (2015). This paper identifies a LTB 4 –neutrophil elastase pathway that cleaves endothelial JAMC, leading to neutrophil rTEM and systemic inflammation.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Beyrau, M., Bodkin, J. V. & Nourshargh, S. Neutrophil heterogeneity in health and disease: a revitalized avenue in inflammation and immunity. Open Biol. 2, 120134 (2012).

    PubMed  PubMed Central  Google Scholar 

  121. Holmes, G. R. et al. Drift-diffusion analysis of neutrophil migration during inflammation resolution in a zebrafish model. Adv. Hematol. 2012, 792163 (2012).

    PubMed  PubMed Central  Google Scholar 

  122. Holmes, G. R. et al. Repelled from the wound, or randomly dispersed? Reverse migration behaviour of neutrophils characterized by dynamic modelling. J. R. Soc., Interface 9, 3229–3239 (2012). This report provides evidence that reverse migration of zebrafish neutrophils in vivo may represent a stochastic redistribution.

    Google Scholar 

  123. Sadik, C. D., Kim, N. D. & Luster, A. D. Neutrophils cascading their way to inflammation. Trends Immunol. 32, 452–460 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Tsukamoto, T., Chanthaphavong, R. S. & Pape, H.-C. C. Current theories on the pathophysiology of multiple organ failure after trauma. Injury 41, 21–26 (2010).

    PubMed  Google Scholar 

  125. Wu, D. et al. Reverse-migrated neutrophils regulated by JAM-C are involved in acute pancreatitis-associated lung injury. Sci. Rep. 6, 20545 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Hampton, H. R., Bailey, J., Tomura, M., Brink, R. & Chtanova, T. Microbe-dependent lymphatic migration of neutrophils modulates lymphocyte proliferation in lymph nodes. Nat. Commun. 6, 7139 (2015). This report shows that photoconverted neutrophils migrate from inflamed skin to lymph nodes via the lymphatic circulation.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Abadie, V. et al. Neutrophils rapidly migrate via lymphatics after Mycobacterium bovis BCG intradermal vaccination and shuttle live bacilli to the draining lymph nodes. Blood 106, 1843–1850 (2005).

    CAS  PubMed  Google Scholar 

  128. Maletto, B. A. et al. Presence of neutrophil-bearing antigen in lymphoid organs of immune mice. Blood 108, 3094–3102 (2006).

    CAS  PubMed  Google Scholar 

  129. Wright, H. L., Moots, R. J. & Edwards, S. W. The multifactorial role of neutrophils in rheumatoid arthritis. Nat. Rev. Rheumatol. 10, 593–601 (2014).

    CAS  PubMed  Google Scholar 

  130. Cantin, A. M. M., Hartl, D., Konstan, M. W. & Chmiel, J. F. Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy. J. Cyst. Fibros. 14, 419–430 (2015).

    CAS  PubMed  Google Scholar 

  131. Cocco, G., Chu, D. C. C. & Pandolfi, S. Colchicine in clinical medicine. A guide for internists. Eur. J. Internal Med. 21, 503–508 (2010).

    CAS  Google Scholar 

  132. Lazaar, A. L. et al. SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans. Br. J. Clin. Pharmacol. 72, 282–293 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Moss, R. B. et al. Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis. J. Cyst. Fibros. 12, 241–248 (2013).

    CAS  PubMed  Google Scholar 

  134. Horuk, R. Chemokine receptor antagonists: overcoming developmental hurdles. Nat. Rev. Drug Discov. 8, 23–33 (2009).

    CAS  PubMed  Google Scholar 

  135. Dalli, J. et al. Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents. Chem. Biol. 20, 188–201 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Eickmeier, O. et al. Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury. Mucosal Immunol. 6, 256–266 (2013).

    CAS  PubMed  Google Scholar 

  137. Schwab, J. M., Chiang, N., Arita, M. & Serhan, C. N. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447, 869–874 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Dovi, J. V., He, L.-K. K. & DiPietro, L. A. Accelerated wound closure in neutrophil-depleted mice. J. Leukoc. Biol. 73, 448–455 (2003).

    CAS  PubMed  Google Scholar 

  139. Li, L., Yan, B., Shi, Y.-Q. Q., Zhang, W.-Q. Q. & Wen, Z.-L. L. Live imaging reveals differing roles of macrophages and neutrophils during zebrafish tail fin regeneration. J. Biol. Chem. 287, 25353–25360 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Paoliello-Paschoalato, A. B. et al. Isolation of healthy individuals' and rheumatoid arthritis patients' peripheral blood neutrophils by the gelatin and Ficoll-Hypaque methods: comparative efficiency and impact on the neutrophil oxidative metabolism and Fcγ receptor expression. J. Immunol. Methods 412, 70–77 (2014).

    CAS  PubMed  Google Scholar 

  141. Collins, S. J., Ruscetti, F. W., Gallagher, R. E. & Gallo, R. C. Terminal differentiation of human promyelocytic leukemia cells induced by dimethyl sulfoxide and other polar compounds. Proc. Natl Acad. Sci. USA 75, 2458–2462 (1978).

    CAS  PubMed  Google Scholar 

  142. Tucker, K. A., Lilly, M. B., Heck, L. & Rado, T. A. Characterization of a new human diploid myeloid leukemia cell line (PLB-985) with granulocytic and monocytic differentiating capacity. Blood 70, 372–378 (1987).

    CAS  PubMed  Google Scholar 

  143. Berthier, E., Surfus, J., Verbsky, J., Huttenlocher, A. & Beebe, D. An arrayed high-content chemotaxis assay for patient diagnosis. Integr. Biol. 2, 630–638 (2010).

    CAS  Google Scholar 

  144. Montanez-Sauri, S. I., Beebe, D. J. & Sung, K. E. Microscale screening systems for 3D cellular microenvironments: platforms, advances, and challenges. Cell. Mol. Life Sci. 72, 237–249 (2015).

    CAS  PubMed  Google Scholar 

  145. Boneschansker, L., Yan, J., Wong, E., Briscoe, D. M. & Irimia, D. Microfluidic platform for the quantitative analysis of leukocyte migration signatures. Nat. Commun. 5, 4787 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Yamahashi, Y. et al. Integrin associated proteins differentially regulate neutrophil polarity and directed migration in 2D and 3D. Biomed. Microdevices 17, 100 (2015).

    PubMed  PubMed Central  Google Scholar 

  147. Mantopoulos, D., Cruzat, A. & Hamrah, P. In vivo imaging of corneal inflammation: new tools for clinical practice and research. Semin. Ophthalmol. 25, 178–185 (2010).

    PubMed  PubMed Central  Google Scholar 

  148. Ley, K. et al. Sequential contribution of L- and P-selectin to leukocyte rolling in vivo. J. Exp. Med. 181, 669–675 (1995).

    CAS  PubMed  Google Scholar 

  149. Zarbock, A., Lowell, C. A. & Ley, K. Spleen tyrosine kinase Syk is necessary for E-selectin-induced αLβ2 integrin-mediated rolling on intercellular adhesion molecule-1. Immunity 26, 773–783 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Emre, Y., Jemelin, S. & Imhof, B. A. Imaging neutrophils and monocytes in mesenteric veins by intravital microscopy on anaesthetized mice in real time. J. Vis. Exp. 105 http://dx.doi.org/10.3791/53314 (2015).

  151. Jenne, C. N., Wong, C. H., Petri, B. & Kubes, P. The use of spinning-disk confocal microscopy for the intravital analysis of platelet dynamics in response to systemic and local inflammation. PLoS ONE 6, e25109 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Looney, M. R. et al. Stabilized imaging of immune surveillance in the mouse lung. Nat. Methods 8, 91–96 (2011).

    CAS  PubMed  Google Scholar 

  153. Wong, J. et al. A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. J. Clin. Invest. 99, 2782–2790 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Slaba, I. et al. Imaging the dynamic platelet-neutrophil response in sterile liver injury and repair in mice. Hepathology 62, 1593–1605 (2015).

    CAS  Google Scholar 

  155. Walters, K. B., Green, J. M., Surfus, J. C., Yoo, S. K. & Huttenlocher, A. Live imaging of neutrophil motility in a zebrafish model of WHIM syndrome. Blood 116, 2803–2811 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Deng, Q., Yoo, S. K., Cavnar, P. J., Green, J. M. & Huttenlocher, A. Dual roles for Rac2 in neutrophil motility and active retention in zebrafish hematopoietic tissue. Dev. Cell 21, 735–745 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Henry, K. M., Loynes, C. A., Whyte, M. K. & Renshaw, S. A. Zebrafish as a model for the study of neutrophil biology. J. Leukoc. Biol. 94, 633–642 (2013).

    CAS  PubMed  Google Scholar 

  158. Lieschke, G. J., Oates, A. C., Crowhurst, M. O., Ward, A. C. & Layton, J. E. Morphologic and functional characterization of granulocytes and macrophages in embryonic and adult zebrafish. Blood 98, 3087–3096 (2001).

    CAS  PubMed  Google Scholar 

  159. Harvie, E. A. & Huttenlocher, A. Neutrophils in host defense: new insights from zebrafish. J. Leukoc. Biol. 98, 523–537 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Berthier, E. et al. Low-volume toolbox for the discovery of immunosuppressive fungal secondary metabolites. PLoS Pathog. 9, e1003289 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Graziano, B. R. & Weiner, O. D. Self-organization of protrusions and polarity during eukaryotic chemotaxis. Curr. Opin. Cell Biol. 30, 60–67 (2014).

    CAS  PubMed  Google Scholar 

  162. Deng, Q. & Huttenlocher, A. Leukocyte migration from a fish eye's view. J. Cell Sci. 125, 3949–3956 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Baker, M. J., Pan, D. & Welch, H. C. Small GTPases and their guanine-nucleotide exchange factors and GTPase-activating proteins in neutrophil recruitment. Curr. Opin. Hematol. 23, 44–54 (2016).

    CAS  PubMed  Google Scholar 

  164. Mócsai, A., Walzog, B. & Lowell, C. A. Intracellular signalling during neutrophil recruitment. Cardiovasc. Res. 107, 373–385 (2015).

    PubMed  PubMed Central  Google Scholar 

  165. Weiner, O. D. Regulation of cell polarity during eukaryotic chemotaxis: the chemotactic compass. Curr. Opin. Cell Biol. 14, 196–202 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Kölsch, V., Charest, P. G. & Firtel, R. A. The regulation of cell motility and chemotaxis by phospholipid signaling. J. Cell Sci. 121, 551–559 (2008).

    PubMed  PubMed Central  Google Scholar 

  167. Afonso, P. V. & Parent, C. A. PI3K and chemotaxis: a priming issue? Sci. Signal. 4, pe22 (2011).

    PubMed  Google Scholar 

  168. Kunisaki, Y. et al. DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis. J. Cell Biol. 174, 647–652 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Welch, H. C. et al. P-Rex1, a PtdIns(3,4,5)P3- and Gβγ-regulated guanine-nucleotide exchange factor for Rac. Cell 108, 809–821 (2002).

    CAS  PubMed  Google Scholar 

  170. Heit, B., Tavener, S., Raharjo, E. & Kubes, P. An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients. J. Cell Biol. 159, 91–102 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Raghuwanshi, S. K. et al. The chemokine receptors CXCR1 and CXCR2 couple to distinct G protein-coupled receptor kinases to mediate and regulate leukocyte functions. J. Immunol. 189, 2824–2832 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Yoo, S. K. et al. Differential regulation of protrusion and polarity by PI3K during neutrophil motility in live zebrafish. Dev. Cell 18, 226–236 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Beerman, R. W. et al. Direct in vivo manipulation and imaging of calcium transients in neutrophils identify a critical role for leading-edge calcium flux. Cell Rep. 13, 2107–2117 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Hu, N. et al. Differential expression of granulopoiesis related genes in neutrophil subsets distinguished by membrane expression of CD177. PLoS ONE 9, e99671 (2014).

    PubMed  PubMed Central  Google Scholar 

  175. Welin, A. et al. The human neutrophil subsets defined by the presence or absence of OLFM4 both transmigrate into tissue in vivo and give rise to distinct NETs in vitro. PLoS ONE 8, e69575 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Hartl, D. et al. Infiltrated neutrophils acquire novel chemokine receptor expression and chemokine responsiveness in chronic inflammatory lung diseases. J. Immunol. 181, 8053–8067 (2008).

    CAS  PubMed  Google Scholar 

  178. Tirouvanziam, R. et al. Profound functional and signaling changes in viable inflammatory neutrophils homing to cystic fibrosis airways. Proc. Natl Acad. Sci. USA 105, 4335–4339 (2008).

    CAS  PubMed  Google Scholar 

  179. Bauer, S. et al. Proteinase 3 and CD177 are expressed on the plasma membrane of the same subset of neutrophils. J. Leukoc. Biol. 81, 458–464 (2007).

    CAS  PubMed  Google Scholar 

  180. Carmona-Rivera, C. & Kaplan, M. J. Low-density granulocytes: a distinct class of neutrophils in systemic autoimmunity. Semin. Immunopathol. 35, 455–463 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Drifte, G., Dunn-Siegrist, I., Tissières, P. & Pugin, J. Innate immune functions of immature neutrophils in patients with sepsis and severe systemic inflammatory response syndrome. Crit. Care Med. 41, 820–832 (2013).

    CAS  PubMed  Google Scholar 

  182. Bowers, N. L. et al. Immune suppression by neutrophils in HIV-1 infection: role of PD-L1/PD-1 pathway. PLoS Pathog. 10, e1003993 (2014).

    PubMed  PubMed Central  Google Scholar 

  183. Cloke, T. et al. Phenotypic alteration of neutrophils in the blood of HIV seropositive patients. PLoS ONE 8, e72034 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Matsushima, H. et al. Neutrophil differentiation into a unique hybrid population exhibiting dual phenotype and functionality of neutrophils and dendritic cells. Blood 121, 1677–1689 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Nair, P. et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin. Exp. Allergy 42, 1097–1103 (2012).

    CAS  PubMed  Google Scholar 

  186. Opfermann, P. et al. A pilot study on reparixin, a CXCR1/2 antagonist, to assess safety and efficacy in attenuating ischaemia-reperfusion injury and inflammation after on-pump coronary artery bypass graft surgery. Clin. Exp. Immunol. 180, 131–142 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Bertini, R. et al. Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor. Br. J. Pharmacol. 165, 436–454 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Leaker, B. R., Barnes, P. J. & O'Connor, B. Inhibition of LPS-induced airway neutrophilic inflammation in healthy volunteers with an oral CXCR2 antagonist. Respiratory Res. 14, 137 (2013)

    Google Scholar 

  189. Miller, B. E. et al. The pharmacokinetics and pharmacodynamics of danirixin (GSK1325756) —a selective CXCR2 antagonist —in healthy adult subjects. BMC Pharmacol. Toxicol. 16, 18 (2015).

    PubMed  PubMed Central  Google Scholar 

  190. Jurcevic, S. et al. The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions. Br. J. Clin. Pharmacol. 80, 1324–1336 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Nicholls, D. J. et al. Pharmacological characterization of AZD5069, a slowly reversible CXC chemokine receptor 2 antagonist. J. Pharmacol. Exp. Ther. 353, 340–350 (2015).

    CAS  PubMed  Google Scholar 

  192. US National Library of Medicine. ClinicalTrials.gov [online], (2016).

  193. US National Library of Medicine. ClinicalTrials.gov [online], (2015).

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Acknowledgements

This work was supported by US National Institutes of Health grant GM074827 to A.H. E.E.R. is supported by an individual fellowship from National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health under award number F32AI113956 and S.D.O. is supported by a European Molecular Biology Organization (EMBO) fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Glossary

Reactive oxygen species

(ROS). Chemically reactive molecules containing oxygen that, when produced in large amounts, have pro-inflammatory and antimicrobial effects. Physiological levels of ROS have been shown to regulate cellular signalling pathways.

Neutrophil extracellular traps

(NETs). Fibrous networks that are released into the extracellular environment by neutrophils. They are mainly composed of DNA but also contain chromatin and proteins from neutrophil granules. NETs function as a mesh that traps microorganisms and exposes them to neutrophil-derived effector molecules.

Neutrophil reverse migration

The movement of neutrophils away from injured tissues within the interstitium.

Damage-associated molecular patterns

(DAMPs). Cues that are derived from stressed, damaged or dead cells. These factors are highly diffusible through tissues and can be protein-derived or non-protein-derived.

Pathogen-associated molecular patterns

(PAMPs). Molecules that are derived from pathogens such as bacteria, fungi or viruses. They readily diffuse through tissues and can be protein-derived or non-protein-derived.

Reverse transendothelial migration

(rTEM). The movement of neutrophils back into the vasculature after being in tissues.

Fugetaxis

Also known as retrotaxis. The movement of cells away from a source of chemoattractant in vitro.

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de Oliveira, S., Rosowski, E. & Huttenlocher, A. Neutrophil migration in infection and wound repair: going forward in reverse. Nat Rev Immunol 16, 378–391 (2016). https://doi.org/10.1038/nri.2016.49

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