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  • Review Article
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Neutrophil recruitment and function in health and inflammation

Key Points

  • The current view of the neutrophil as a short-lived, homogeneous cell type with a role limited to the elimination of pathogens during the innate immune response has begun to change. Recent studies have revealed that the lifespan of a neutrophil in circulation might be much longer, and that differential subpopulations of neutrophils and their reservoirs (marginal pools) might exist (although it still remains to be determined whether these subpopulations are functional or lineage-restricted).

  • The classical cascade of neutrophil recruitment has been updated recently to reflect our better understanding of how this process occurs in the blood under shear stress conditions (for example, neutrophils have been found to form tethers and slings to anchor themselves to the vasculature). In addition, our understanding has improved regarding what are preferable sites of neutrophil extravasation. It is also now clear that there are exceptions to this classical cascade in a number of organs, such as the liver, lung and brain, where some steps of the cascade do not occur and/or different molecules are used by neutrophils. Furthermore, we recognize there might be differences between sterile and infectious inflammation.

  • Once extravasated, neutrophils follow a hierarchy of chemotactic molecules to reach the site of inflammation, following first 'intermediate' chemoattractants (endogenous chemokines) and then later 'end-target' chemoattractants (bacterial peptides or complement components). The process of chemotaxis is controlled by multiple intracellular signalling pathways (mitogen-activated protein kinase-dependent) controlling 'go' and 'stop' signals.

  • Despite the pre-existing dogma that neutrophils leave the vasculature and die, it has been revealed that some extravasated neutrophils might re-enter circulation, leading to the dissemination of inflammation to other organs and subsequent tissue injury. In other cases, transmigrating cells may play an important part in the resolution of inflammation. In fact, neutrophils were shown to participate in wound healing and to actively limit self-recruitment through the release of endogenous molecules that inhibit integrin activation or cytoskeletal changes.

  • Newly described roles of neutrophils cover their involvement in adaptive immunity by controlling the activation of T and B cells, and through the presentation of antigens to professional antigen-presenting cells in lymph nodes.

  • Neutrophil extracellular trap (NET) formation, a strategy of pathogen eradication discovered less than a decade ago, has now been described to occur in vivo not only during acute (bacterial or viral) inflammation but also in numerous pathological conditions, such as autoimmune diseases, vascular diseases and cancer. Recently described mechanisms of NET formation indicate that neutrophils releasing NETs in vivo do not immediately die but rather keep performing functions such as chemotaxis and phagocytosis.

Abstract

Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti-inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites.

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Figure 1: The updated classical neutrophil recruitment cascade.
Figure 2: Mechanisms of formation and engagement of tethers and slings by rolling neutrophils.
Figure 3: Migrating neutrophils actively choose sites of transmigration.

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References

  1. Phillipson, M. & Kubes, P. The neutrophil in vascular inflammation. Nature Med. 17, 1381–1390 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Ley, K., Laudanna, C., Cybulsky, M. I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature Rev. Immunol. 7, 678–689 (2007).

    Article  CAS  Google Scholar 

  3. Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004). The first report on the existence of NETs, in which the authors outline NET characteristics and functions.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Amulic, B., Cazalet, C., Hayes, G. L., Metzler, K. D. & Zychlinsky, A. Neutrophil function: from mechanisms to disease. Annu. Rev. Immunol. 30, 459–489 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Mantovani, A., Cassatella, M. A., Costantini, C. & Jaillon, S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nature Rev. Immunol. 11, 519–531 (2011).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Zeidler, C., Germeshausen, M., Klein, C. & Welte, K. Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia. Br. J. Haematol. 144, 459–467 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Dotta, L., Tassone, L. & Badolato, R. Clinical and genetic features of warts, hypoγglobulinemia, infections and myelokathexis (WHIM) syndrome. Curr. Mol. Med. 11, 317–325 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Pillay, J. et al. In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood 116, 625–627 (2010). This paper reported on the unexpectedly long lifespan of human neutrophils (>5 days). References 12 and 13 address critical concerns.

    Article  CAS  PubMed  Google Scholar 

  11. Galli, S. J., Borregaard, N. & Wynn, T. A. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nature Immunol. 12, 1035–1044 (2011).

    Article  CAS  Google Scholar 

  12. Tofts, P. S., Chevassut, T., Cutajar, M., Dowell, N. G. & Peters, A. M. Doubts concerning the recently reported human neutrophil lifespan of 5.4 days. Blood 117, 6050–6052; author reply 6053–6054 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Li, K. W., Turner, S. M., Emson, C. L., Hellerstein, M. K. & Dale, D. C. Deuterium and neutrophil kinetics. Blood 117, 6052–6053; author reply 6053–6054 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Summers, C. et al. Neutrophil kinetics in health and disease. Trends Immunol. 31, 318–324 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Colotta, F., Re, F., Polentarutti, N., Sozzani, S. & Mantovani, A. Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products. Blood 80, 2012–2020 (1992).

    CAS  PubMed  Google Scholar 

  16. Kim, M. H. et al. Neutrophil survival and c-kit+-progenitor proliferation in Staphylococcus aureus-infected skin wounds promote resolution. Blood 117, 3343–3352 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. De Santo, C. et al. Invariant NKT cells modulate the suppressive activity of IL-10-secreting neutrophils differentiated with serum amyloid A. Nature Immunol. 11, 1039–1046 (2010).

    Article  CAS  Google Scholar 

  18. Mauer, A. M., Athens, J. W., Ashenbrucker, H., Cartwright, G. E. & Wintrobe, M. M. Leukokinetic studies. Ii. A method for labeling granulocytes in vitro with radioactive diisopropylfluorophosphate (Dfp). J. Clin. Invest. 39, 1481–1486 (1960).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Peters, A. M. Just how big is the pulmonary granulocyte pool? Clin. Sci. (Lond.) 94, 7–19 (1998).

    Article  CAS  Google Scholar 

  20. Sibille, Y. & Marchandise, F. X. Pulmonary immune cells in health and disease: polymorphonuclear neutrophils. Eur. Respir. J. 6, 1529–1543 (1993).

    CAS  PubMed  Google Scholar 

  21. Peters, A. M., Saverymuttu, S. H., Keshavarzian, A., Bell, R. N. & Lavender, J. P. Splenic pooling of granulocytes. Clin. Sci. (Lond.) 68, 283–289 (1985).

    Article  CAS  Google Scholar 

  22. Ussov, W. Y., Aktolun, C., Myers, M. J., Jamar, F. & Peters, A. M. Granulocyte margination in bone marrow: comparison with margination in the spleen and liver. Scand. J. Clin. Lab Invest. 55, 87–96 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Lien, D. C. et al. Physiological neutrophil sequestration in the lung: visual evidence for localization in capillaries. J. Appl. Physiol. 62, 1236–1243 (1987).

    Article  CAS  PubMed  Google Scholar 

  24. Megens, R. T., Kemmerich, K., Pyta, J., Weber, C. & Soehnlein, O. Intravital imaging of phagocyte recruitment. Thromb. Haemost. 105, 802–810 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Hong, C. et al. Coordinate regulation of neutrophil homeostasis by liver X receptors in mice. J. Clin. Invest. 122, 337–347 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Shi, J., Gilbert, G. E., Kokubo, Y. & Ohashi, T. Role of the liver in regulating numbers of circulating neutrophils. Blood 98, 1226–1230 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Eash, K. J., Means, J. M., White, D. W. & Link, D. C. CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions. Blood 113, 4711–4719 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kubes, P., Hunter, J. & Granger, D. N. Ischemia/reperfusion-induced feline intestinal dysfunction: importance of granulocyte recruitment. Gastroenterology 103, 807–812 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. Stark, M. A. et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285–294 (2005). This report identified a cytokine axis regulating the removal of apoptotic neutrophils from tissues and the induction of granulopoiesis.

    Article  CAS  PubMed  Google Scholar 

  31. McDonald, B., Urrutia, R., Yipp, B. G., Jenne, C. N. & Kubes, P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 12, 324–333 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Yipp, B. G. et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nature Med. 18, 1386–1393 (2012). This article demonstrated that neutrophils releasing NETs do not immediately die and keep performing chemotaxis and phagocytosis.

    Article  CAS  PubMed  Google Scholar 

  33. Tsuda, Y. et al. Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus. Immunity 21, 215–226 (2004). The first report on different neutrophil subpopulations; see also subsequent reports in references 34–37.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pillay, J. et al. Functional heterogeneity and differential priming of circulating neutrophils in human experimental endotoxemia. J. Leukoc. Biol. 88, 211–220 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Kamp, V. M. et al. Human suppressive neutrophils CD16bright/CD62Ldim exhibit decreased adhesion. J. Leukoc. Biol. 92, 1011–1020 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Puga, I. et al. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nature Immunol. 13, 170–180 (2012).

    Article  CAS  Google Scholar 

  38. Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 122, 787–795 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pillay, J. et al. A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1. J. Clin. Invest. 122, 327–336 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Johnston, B. et al. Chronic inflammation upregulates chemokine receptors and induces neutrophil migration to monocyte chemoattractant protein-1. J. Clin. Invest. 103, 1269–1276 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tosello Boari, J. et al. IL-17RA signaling reduces inflammation and mortality during Trypanosoma cruzi infection by recruiting suppressive IL-10-producing neutrophils. PLoS Pathog. 8, e1002658 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhang, X., Majlessi, L., Deriaud, E., Leclerc, C. & Lo-Man, R. Coactivation of Syk kinase and MyD88 adaptor protein pathways by bacteria promotes regulatory properties of neutrophils. Immunity 31, 761–771 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Christoffersson, G. et al. VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue. Blood 120, 4653–4662 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jablonska, J., Leschner, S., Westphal, K., Lienenklaus, S. & Weiss, S. Neutrophils responsive to endogenous IFN-β regulate tumor angiogenesis and growth in a mouse tumor model. J. Clin. Invest. 120, 1151–1164 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Petri, B., Phillipson, M. & Kubes, P. The physiology of leukocyte recruitment: an in vivo perspective. J. Immunol. 180, 6439–6446 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Zarbock, A., Ley, K., McEver, R. P. & Hidalgo, A. Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow. Blood 118, 6743–6751 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Arbones, M. L. et al. Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice. Immunity 1, 247–260 (1994).

    Article  CAS  PubMed  Google Scholar 

  48. Bargatze, R. F., Kurk, S., Butcher, E. C. & Jutila, M. A. Neutrophils roll on adherent neutrophils bound to cytokine-induced endothelial cells via L-selectin on the rolling cells. J. Exp. Med. 180, 1785–1792 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Sundd, P. et al. 'Slings' enable neutrophil rolling at high shear. Nature 488, 399–403 (2012). This report describes mechanisms of tether and sling formation under shear stress in blood vessels.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sundd, P., Pospieszalska, M. K., Cheung, L. S., Konstantopoulos, K. & Ley, K. Biomechanics of leukocyte rolling. Biorheology 48, 1–35 (2011).

    PubMed  PubMed Central  Google Scholar 

  51. Ramachandran, V., Williams, M., Yago, T., Schmidtke, D. W. & McEver, R. P. Dynamic alterations of membrane tethers stabilize leukocyte rolling on P-selectin. Proc. Natl Acad. Sci. USA 101, 13519–13524 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Khismatullin, D. B. & Truskey, G. A. Leukocyte rolling on p-selectin: a three-dimensional numerical study of the effect of cytoplasmic viscosity. Biophys. J. 102, 1757–1766 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sundd, P. et al. Quantitative dynamic footprinting microscopy reveals mechanisms of neutrophil rolling. Nature Methods 7, 821–824 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Schmidtke, D. W. & Diamond, S. L. Direct observation of membrane tethers formed during neutrophil attachment to platelets or P-selectin under physiological flow. J. Cell Biol. 149, 719–730 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Guthrie, L. A., McPhail, L. C., Henson, P. M. & Johnston, R. B. Jr. Priming of neutrophils for enhanced release of oxygen metabolites by bacterial lipopolysaccharide. Evidence for increased activity of the superoxide-producing enzyme. J. Exp. Med. 160, 1656–1671 (1984).

    Article  CAS  PubMed  Google Scholar 

  56. Sanz, M. J. & Kubes, P. Neutrophil-active chemokines in in vivo imaging of neutrophil trafficking. Eur. J. Immunol. 42, 278–283 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Williams, M. R., Azcutia, V., Newton, G., Alcaide, P. & Luscinskas, F. W. Emerging mechanisms of neutrophil recruitment across endothelium. Trends Immunol. 32, 461–469 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pruenster, M. et al. The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity. Nature Immunol. 10, 101–108 (2009).

    Article  CAS  Google Scholar 

  59. Wang, L., Fuster, M. Sriramarao, P. & Esko, J. D. Endothelial heparan sulfate deficiency impairs L-selectin- and chemokine-mediated neutrophil trafficking during inflammatory responses. Nature Immunol. 6, 902–910 (2005).

    Article  CAS  Google Scholar 

  60. Massena, S. et al. A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils. Blood 116, 1924–1931 (2010). The paper explains how the intravascular chemotactic gradient stays attached to endothelium.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hillyer, P. & Male, D. Expression of chemokines on the surface of different human endothelia. Immunol. Cell Biol. 83, 375–382 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Phillipson, M. et al. Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J. Exp. Med. 203, 2569–2575 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Jones, D. H. et al. Quantitation of intracellular Mac-1 (CD11b/CD18) pools in human neutrophils. J. Leukoc. Biol. 44, 535–544 (1988).

    Article  CAS  PubMed  Google Scholar 

  64. Lefort, C. T. et al. Distinct roles for talin-1 and kindlin-3 in LFA-1 extension and affinity regulation. Blood 119, 4275–4282 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Cicchetti, G., Allen, P. G. & Glogauer, M. Chemotactic signaling pathways in neutrophils: from receptor to actin assembly. Crit. Rev. Oral Biol. Med. 13, 220–228 (2002).

    Article  PubMed  Google Scholar 

  66. Phillipson, M. et al. Vav1 is essential for mechanotactic crawling and migration of neutrophils out of the inflamed microvasculature. J. Immunol. 182, 6870–6878 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. McDonald, B. et al. Interaction of CD44 and hyaluronan is the dominant mechanism for neutrophil sequestration in inflamed liver sinusoids. J. Exp. Med. 205, 915–927 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  69. Wisse, E., De Zanger, R. B., Charels, K., Van Der Smissen, P. & McCuskey, R. S. The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology 5, 683–692 (1985).

    Article  CAS  PubMed  Google Scholar 

  70. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Menezes, G. B. et al. Selective down-regulation of neutrophil Mac-1 in endotoxemic hepatic microcirculation via IL-10. J. Immunol. 183, 7557–7568 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  73. Carvalho-Tavares, J. et al. A role for platelets and endothelial selectins in tumor necrosis factor-α-induced leukocyte recruitment in the brain microvasculature. Circ. Res. 87, 1141–1148 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Ostrovsky, L. et al. A juxtacrine mechanism for neutrophil adhesion on platelets involves platelet-activating factor and a selectin-dependent activation process. Blood 91, 3028–3036 (1998).

    CAS  PubMed  Google Scholar 

  75. Drechsler, M., Megens, R. T., van Zandvoort, M., Weber, C. & Soehnlein, O. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation 122, 1837–1845 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Saiwai, H. et al. The LTB4-BLT1 axis mediates neutrophil infiltration and secondary injury in experimental spinal cord injury. Am. J. Pathol. 176, 2352–2366 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Oyoshi, M. K. et al. Leukotriene B4-driven neutrophil recruitment to the skin is essential for allergic skin inflammation. Immunity 37, 747–758 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. da Silva, J. B. et al. Induction of TNF-α and CXCL-2 mRNAs in different organs of mice infected with pathogenic Leptospira. Microb. Pathog. 52, 206–216 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Jenne, C. N. et al. Intravital visualization of a protective innate immune response to challenge from an acute viral infection. Cell Host Microbe (in the press).

  81. Dewey, C. F. Jr., Bussolari, S. R., Gimbrone, M. A. Jr & Davies, P. F. The dynamic response of vascular endothelial cells to fluid shear stress. J. Biomech. Eng. 103, 177–185 (1981).

    Article  PubMed  Google Scholar 

  82. Hepper, I. et al. The mammalian actin-binding protein 1 is critical for spreading and intraluminal crawling of neutrophils under flow conditions. J. Immunol. 188, 4590–4601 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Petri, B. et al. Endothelial LSP1 is involved in endothelial dome formation, minimizing vascular permeability changes during neutrophil transmigration in vivo. Blood 117, 942–952 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Reymond, N. et al. DNAM-1 and PVR regulate monocyte migration through endothelial junctions. J. Exp. Med. 199, 1331–1341 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Burns, A. R. et al. Analysis of tight junctions during neutrophil transendothelial migration. J. Cell Sci. 113, 45–57 (2000).

    CAS  PubMed  Google Scholar 

  86. Woodfin, A. et al. The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo. Nature Immunol. 12, 761–769 (2011).

    Article  CAS  Google Scholar 

  87. Phillipson, M., Kaur, J., Colarusso, P., Ballantyne, C. M. & Kubes, P. Endothelial domes encapsulate adherent neutrophils and minimize increases in vascular permeability in paracellular and transcellular emigration. PLoS ONE 3, e1649 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Barreiro, O. et al. Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J. Cell Biol. 157, 1233–1245 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Carman, C. V. & Springer, T. A. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J. Cell Biol. 167, 377–388 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Feng, D., Nagy, J. A., Pyne, K., Dvorak, H. F. & Dvorak, A. M. Neutrophils emigrate from venules by a transendothelial cell pathway in response to FMLP. J. Exp. Med. 187, 903–915 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sage, P. T. & Carman, C. V. Settings and mechanisms for trans-cellular diapedesis. Front. Biosci. 14, 5066–5083 (2009).

    Article  CAS  PubMed Central  Google Scholar 

  92. Parsons, S. A. et al. Endothelial paxillin and focal adhesion kinase (FAK) play a critical role in neutrophil transmigration. Eur. J. Immunol. 42, 436–446 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Kolaczkowska, E. et al. Neutrophil elastase activity compensates for a genetic lack of matrix metalloproteinase-9 (MMP-9) in leukocyte infiltration in a model of experimental peritonitis. J. Leukoc. Biol. 85, 374–381 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Betsuyaku, T., Shipley, J. M., Liu, Z. & Senior, R. M. Neutrophil emigration in the lungs, peritoneum, and skin does not require gelatinase B. Am. J. Respir. Cell. Mol. Biol. 20, 1303–1309 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Wang, S. et al. Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils. J. Exp. Med. 203, 1519–1532 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kuckleburg, C. J., Tilkens, S. B., Santoso, S. & Newman, P. J. Proteinase 3 contributes to transendothelial migration of NB1-positive neutrophils. J. Immunol. 188, 2419–2426 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Hurley, J. V. An electron microscopic study of leucocytic emigration and vascular permeability in rat skin. Aust. J. Exp. Biol. Med. Sci. 41, 171–186 (1963).

    Article  CAS  PubMed  Google Scholar 

  98. Marchesi, V. T. & Florey, H. W. Electron micrographic observations on the emigration of leucocytes. Q. J. Exp. Physiol. Cogn. Med. Sci. 45, 343–348 (1960).

    CAS  PubMed  Google Scholar 

  99. Proebstl, D. et al. Pericytes support neutrophil subendothelial cell crawling and breaching of venular walls in vivo. J. Exp. Med. 209, 1219–1234 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Stark, K. et al. Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and 'instruct' them with pattern-recognition and motility programs. Nature Immunol. 14, 41–51 (2013). This paper shows that pericytes surrounding endothelial cells actively regulate the extravasation of neutrophils and their direct migration to the site of inflammation.

    Article  CAS  Google Scholar 

  101. Foxman, E. F., Campbell, J. J. & Butcher, E. C. Multistep navigation and the combinatorial control of leukocyte chemotaxis. J. Cell Biol. 139, 1349–1360 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Funamoto, S., Meili, R., Lee, S., Parry, L. & Firtel, R. A. Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell 109, 611–623 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Heit, B. et al. PTEN functions to 'prioritize' chemotactic cues and prevent 'distraction' in migrating neutrophils. Nature Immunol. 9, 743–752 (2008).

    Article  CAS  Google Scholar 

  104. Quinton, L. J. et al. Selective transport of cytokine-induced neutrophil chemoattractant from the lung to the blood facilitates pulmonary neutrophil recruitment. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L465–L472 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Liu, X. et al. Bidirectional regulation of neutrophil migration by mitogen-activated protein kinases. Nature Immunol. 13, 457–464 (2012). This paper complements data from reference 103 revealing that a balance between ERK and p38 MAPKs controls neutrophil 'stop' and 'go' behaviour during migration.

    Article  CAS  Google Scholar 

  106. Prossnitz, E. R., Kim, C. M., Benovic, J. L. & Ye, R. D. Phosphorylation of the N-formyl peptide receptor carboxyl terminus by the G protein-coupled receptor kinase, GRK2. J. Biol. Chem. 270, 1130–1137 (1995).

    Article  CAS  PubMed  Google Scholar 

  107. Mathias, J. R. et al. Resolution of inflammation by retrograde chemotaxis of neutrophils in transgenic zebrafish. J. Leukoc. Biol. 80, 1281–1288 (2006). This is the first report documenting in vivo that emigrated neutrophils can re-enter the vasculature.

    Article  CAS  PubMed  Google Scholar 

  108. 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).

    Article  CAS  PubMed  Google Scholar 

  109. 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).

    Article  CAS  PubMed  Google Scholar 

  110. Ajuebor, M. N. et al. Role of resident peritoneal macrophages and mast cells in chemokine production and neutrophil migration in acute inflammation: evidence for an inhibitory loop involving endogenous IL-10. J. Immunol. 162, 1685–1691 (1999).

    CAS  PubMed  Google Scholar 

  111. Vieira, S. M. et al. A crucial role for TNF-α in mediating neutrophil influx induced by endogenously generated or exogenous chemokines, KC/CXCL1 and LIX/CXCL5. Br. J. Pharmacol. 158, 779–789 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kawai, T. & Akira, S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637–650 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Matsumoto, M. et al. A novel LPS-inducible C-type lectin is a transcriptional target of NF-IL6 in macrophages. J. Immunol. 163, 5039–5048 (1999).

    CAS  PubMed  Google Scholar 

  114. Yamasaki, S. et al. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nature Immunol. 9, 1179–1188 (2008).

    Article  CAS  Google Scholar 

  115. Scotland, R. S., Stables, M. J., Madalli, S., Watson, P. & Gilroy, D. W. Sex differences in resident immune cell phenotype underlie more efficient acute inflammatory responses in female mice. Blood 118, 5918–5927 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Adrie, C. et al. Influence of gender on the outcome of severe sepsis: a reappraisal. Chest 132, 1786–1793 (2007).

    Article  PubMed  Google Scholar 

  117. Kronenberg, M. & Kinjo, Y. Innate-like recognition of microbes by invariant natural killer T cells. Curr. Opin. Immunol. 21, 391–396 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Brennan, P. J. et al. Invariant natural killer T cells recognize lipid self antigen induced by microbial danger signals. Nature Immunol. 12, 1202–1211 (2011).

    Article  CAS  Google Scholar 

  119. Wintermeyer, P. et al. Invariant natural killer T cells suppress the neutrophil inflammatory response in a mouse model of cholestatic liver damage. Gastroenterology 136, 1048–1059 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Michel, M. L. et al. Identification of an IL-17-producing NK1.1neg iNKT cell population involved in airway neutrophilia. J. Exp. Med. 204, 995–1001 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Lee, W. Y. et al. An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nature Immunol. 11, 295–302 (2010).

    Article  CAS  Google Scholar 

  122. Boilard, E. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 327, 580–583 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Grommes, J. & Soehnlein, O. Contribution of neutrophils to acute lung injury. Mol. Med. 17, 293–307 (2011).

    Article  CAS  PubMed  Google Scholar 

  124. Zarbock, A., Singbartl, K. & Ley, K. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. J. Clin. Invest. 116, 3211–3219 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kornerup, K. N., Salmon, G. P., Pitchford, S. C., Liu, W. L. & Page, C. P. Circulating platelet-neutrophil complexes are important for subsequent neutrophil activation and migration. J. Appl. Physiol. 109, 758–767 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Grommes, J. et al. Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am. J. Respir. Crit. Care Med. 185, 628–636 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Cua, D. J. & Tato, C. M. Innate IL-17-producing cells: the sentinels of the immune system. Nature Rev. Immunol. 10, 479–489 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  129. Krzyzaniak, M. et al. Burn-induced acute lung injury requires a functional Toll-like receptor 4. Shock 36, 24–29 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Chen, G. Y. & Nunez, G. Sterile inflammation: sensing and reacting to damage. Nature Rev. Immunol. 10, 826–837 (2010).

    Article  CAS  Google Scholar 

  131. van Oostrom, A. J., van Wijk, J. P., Sijmonsma, T. P., Rabelink, T. J. & Castro Cabezas, M. Increased expression of activation markers on monocytes and neutrophils in type 2 diabetes. Neth. J. Med. 62, 320–325 (2004).

    CAS  PubMed  Google Scholar 

  132. Kordonowy, L. L. et al. Obesity is associated with neutrophil dysfunction and attenuation of murine acute lung injury. Am. J. Respir. Cell. Mol. Biol. 47, 120–127 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Pini, M. et al. Role and regulation of adipokines during zymosan-induced peritoneal inflammation in mice. Endocrinology 149, 4080–4085 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature Med. 17, 179–188 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. Ye, R. D. et al. International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol. Rev. 61, 119–161 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Fournier, B. M. & Parkos, C. A. The role of neutrophils during intestinal inflammation. Mucosal Immunol. 5, 354–366 (2012).

    Article  CAS  PubMed  Google Scholar 

  137. Cauwe, B., Martens, E., Proost, P. & Opdenakker, G. Multidimensional degradomics identifies systemic autoantigens and intracellular matrix proteins as novel gelatinase B/MMP-9 substrates. Integr. Biol. (Camb.) 1, 404–426 (2009).

    Article  CAS  Google Scholar 

  138. Gong, Y. & Koh, D. R. Neutrophils promote inflammatory angiogenesis via release of preformed VEGF in an in vivo corneal model. Cell Tissue Res. 339, 437–448 (2010).

    Article  PubMed  Google Scholar 

  139. Christoffersson, G. et al. Clinical and experimental pancreatic islet transplantation to striated muscle: establishment of a vascular system similar to that in native islets. Diabetes 59, 2569–2578 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Soehnlein, O. & Lindbom, L. Neutrophil-derived azurocidin alarms the immune system. J. Leukoc. Biol. 85, 344–351 (2009).

    Article  CAS  PubMed  Google Scholar 

  141. Soehnlein, O. et al. Neutrophil secretion products pave the way for inflammatory monocytes. Blood 112, 1461–1471 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Hurst, S. M. et al. Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity 14, 705–714 (2001). This report explains some of the mechanisms leading to the resolution of inflammation. It demonstrates that soluble IL-6 and its soluble receptor regulate chemokine 8 production, leading to the suppression of neutrophil recruitment and the initiation of monocyte recruitment.

    Article  CAS  PubMed  Google Scholar 

  143. Canturk, N. Z. et al. The relationship between neutrophils and incisional wound healing. Skin Pharmacol. Appl. Skin Physiol. 14, 108–116 (2001).

    Article  CAS  PubMed  Google Scholar 

  144. Serhan, C. N. Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not? Am. J. Pathol. 177, 1576–1591 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Sareila, O., Kelkka, T., Pizzolla, A., Hultqvist, M. & Holmdahl, R. NOX2 complex-derived ROS as immune regulators. Antioxid. Redox Signal. 15, 2197–2208 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Perretti, M. & Dalli, J. Exploiting the Annexin A1 pathway for the development of novel anti-inflammatory therapeutics. Br. J. Pharmacol. 158, 936–946 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Serhan, C. N., Chiang, N. & Van Dyke, T. E. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nature Rev. Immunol. 8, 349–361 (2008).

    Article  CAS  Google Scholar 

  148. Aherne, C. M. et al. Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis. Gut 61, 695–705 (2012).

    Article  CAS  PubMed  Google Scholar 

  149. Rosenberger, P. et al. Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nature Immunol. 10, 195–202 (2009).

    Article  CAS  Google Scholar 

  150. Ishii, M. et al. CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis. J. Immunol. 188, 5655–5664 (2012).

    Article  CAS  PubMed  Google Scholar 

  151. Deban, L. et al. Regulation of leukocyte recruitment by the long pentraxin PTX3. Nature Immunol. 11, 328–334 (2010). This paper, along with references 152–155, reported the existence of various endogenous inhibitors of neutrophil recruitment, mostly through the inhibition of selectin or integrin-related events.

    Article  CAS  Google Scholar 

  152. Kempf, T. et al. GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nature Med. 17, 581–588 (2011).

    Article  CAS  PubMed  Google Scholar 

  153. Choi, E. Y. et al. Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science 322, 1101–1104 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Eskan, M. A. et al. The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nature Immunol. 13, 465–473 (2012).

    Article  CAS  Google Scholar 

  155. Wang, J., Shiratori, I., Uehori, J., Ikawa, M. & Arase, H. Neutrophil infiltration during inflammation is regulated by PILRα via modulation of integrin activation. Nature Immunol. 14, 34–40 (2013).

    Article  CAS  Google Scholar 

  156. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Rev. Immunol. 9, 162–174 (2009).

    Article  CAS  Google Scholar 

  157. 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).

    Article  CAS  PubMed  Google Scholar 

  158. Tillack, K., Breiden, P., Martin, R. & Sospedra, M. T lymphocyte priming by neutrophil extracellular traps links innate and adaptive immune responses. J. Immunol. 188, 3150–3159 (2012). One of the newest reports on neutrophil involvement in the regulation of adaptive immunity. This report shows that NETs released by neutrophils can prime T cell responses to specific antigens.

    Article  CAS  PubMed  Google Scholar 

  159. Ellis, T. N. & Beaman, B. L. Murine polymorphonuclear neutrophils produce interferon-γ in response to pulmonary infection with Nocardia asteroides. J. Leukoc. Biol. 72, 373–381 (2002).

    CAS  PubMed  Google Scholar 

  160. Yin, J. & Ferguson, T. A. Identification of an IFN-γ-producing neutrophil early in the response to Listeria monocytogenes. J. Immunol. 182, 7069–7073 (2009).

    Article  CAS  PubMed  Google Scholar 

  161. Beauvillain, C. et al. CCR7 is involved in the migration of neutrophils to lymph nodes. Blood 117, 1196–1204 (2011).

    Article  CAS  PubMed  Google Scholar 

  162. Talukdar, S. et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nature Med. 18, 1407–1412 (2012).

    Article  CAS  PubMed  Google Scholar 

  163. Soehnlein, O. et al. Neutrophil-derived cathelicidin protects from neointimal hyperplasia. Sci. Transl. Med. 3, 103ra98 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  165. Lieschke, G. J. et al. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 84, 1737–1746 (1994).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  167. Nerlov, C. & Graf, T. PU.1 induces myeloid lineage commitment in multipotent hematopoietic progenitors. Genes Dev. 12, 2403–2412 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Dahl, R. et al. Regulation of macrophage and neutrophil cell fates by the PU.1:C/EBPα ratio and granulocyte colony-stimulating factor. Nature Immunol. 4, 1029–1036 (2003).

    Article  CAS  Google Scholar 

  169. Doeing, D. C., Borowicz, J. L. & Crockett, E. T. Gender dimorphism in differential peripheral blood leukocyte counts in mice using cardiac, tail, foot, and saphenous vein puncture methods. BMC Clin. Pathol. 3, 3 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).

    Article  CAS  PubMed  Google Scholar 

  171. Hager, M., Cowland, J. B. & Borregaard, N. Neutrophil granules in health and disease. J. Intern. Med. 268, 25–34 (2010).

    CAS  PubMed  Google Scholar 

  172. Faurschou, M., Sorensen, O. E., Johnsen, A. H., Askaa, J. & Borregaard, N. Defensin-rich granules of human neutrophils: characterization of secretory properties. Biochim. Biophys. Acta 1591, 29–35 (2002).

    Article  CAS  PubMed  Google Scholar 

  173. Borregaard, N., Christensen, L., Bejerrum, O. W., Birgens, H. S. & Clemmensen, I. Identification of a highly mobilizable subset of human neutrophil intracellular vesicles that contains tetranectin and latent alkaline phosphatase. J. Clin. Invest. 85, 408–416 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Papayannopoulos, V. & Zychlinsky, A. NETs: a new strategy for using old weapons. Trends Immunol. 30, 513–521 (2009).

    Article  CAS  PubMed  Google Scholar 

  175. von Kockritz-Blickwede, M. et al. Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. Blood 111, 3070–3080 (2008).

    Article  CAS  PubMed  Google Scholar 

  176. Chow, O. A. et al. Statins enhance formation of phagocyte extracellular traps. Cell Host Microbe 8, 445–454 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Aulik, N. A., Hellenbrand, K. M. & Czuprynski, C. J. Mannheimia haemolytica and its leukotoxin cause macrophage extracellular trap formation by bovine macrophages. Infect. Immun. 80, 1923–1933 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Hawes, M. C. et al. Extracellular DNA: the tip of root defenses? Plant Sci. 180, 741–745 (2011).

    Article  CAS  PubMed  Google Scholar 

  179. Guimaraes-Costa, A. B. et al. Leishmania amazonensis promastigotes induce and are killed by neutrophil extracellular traps. Proc. Natl Acad. Sci. USA 106, 6748–6753 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Menegazzi, R., Decleva, E. & Dri, P. Killing by neutrophil extracellular traps: fact or folklore? Blood 119, 1214–1216 (2012).

    Article  CAS  PubMed  Google Scholar 

  181. Saitoh, T. et al. Neutrophil extracellular traps mediate a host defense response to human immunodeficiency virus-1. Cell Host Microbe 12, 109–116 (2012).

    Article  CAS  PubMed  Google Scholar 

  182. Fuchs, T. A. et al. Novel cell death program leads to neutrophil extracellular traps. J. Cell Biol. 176, 231–241 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Megens, R. T. et al. Presence of luminal neutrophil extracellular traps in atherosclerosis. Thromb. Haemost. 107, 597–598 (2012).

    Article  CAS  PubMed  Google Scholar 

  184. Knight, J. S. & Kaplan, M. J. Lupus neutrophils: 'NET' gain in understanding lupus pathogenesis. Curr. Opin. Rheumatol. 24, 441–450 (2012).

    Article  CAS  PubMed  Google Scholar 

  185. Ray, K. Autoimmunity: disordered NETs implicated in pathogenesis of MPO-ANCA-associated vasculitis. Nature Rev. Rheumatol. 8, 501 (2012).

    Article  Google Scholar 

  186. von Bruhl, M. L. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J. Exp. Med. 209, 819–835 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Caudrillier, A. et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J. Clin. Invest. 122, 2661–2671 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Demers, M. et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc. Natl Acad. Sci. USA 109, 13076–13081 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Kessenbrock, K. et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nature Med. 15, 623–625 (2009).

    Article  CAS  PubMed  Google Scholar 

  190. Mempel, T. R., Scimone, M. L., Mora, J. R. & von Andrian, U. H. In vivo imaging of leukocyte trafficking in blood vessels and tissues. Curr. Opin. Immunol. 16, 406–417 (2004).

    Article  CAS  PubMed  Google Scholar 

  191. Cohnheim, J. Vorlesungen über Allgemeine Pathologie: Ein Handbuch Für Aerzte und Studierende. 2e., neu bearbeitete Auflage. edn, (Verlag von August Hirschwald, 1882).

    Google Scholar 

  192. Atherton, A. & Born, G. V. Quantitative investigations of the adhesiveness of circulating polymorphonuclear leucocytes to blood vessel walls. J. Physiol. 222, 447–474 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. von Andrian, U. H. et al. Two-step model of leukocyte-endothelial cell interaction in inflammation: distinct roles for LECAM-1 and the leukocyte β 2 integrins in vivo. Proc. Natl Acad. Sci. USA 88, 7538–7542 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Ley, K. et al. Lectin-like cell adhesion molecule 1 mediates leukocyte rolling in mesenteric venules in vivo. Blood 77, 2553–2555 (1991).

    CAS  PubMed  Google Scholar 

  195. Kubes, P., Suzuki, M. & Granger, D. N. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc. Natl Acad. Sci. USA 88, 4651–4655 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Mayadas, T. N., Johnson, R. C., Rayburn, H., Hynes, R. O. & Wagner, D. D. Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell 74, 541–554 (1993).

    Article  CAS  PubMed  Google Scholar 

  197. Sumen, C., Mempel, T. R., Mazo, I. B. & von Andrian, U. H. Intravital microscopy: visualizing immunity in context. Immunity 21, 315–329 (2004).

    CAS  PubMed  Google Scholar 

  198. Yipp, B. G. & Kubes, P. Antibodies against neutrophil LY6G do not inhibit leukocyte recruitment in mice in vivo. Blood 121, 241–242 (2013).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The work in the authors' laboratory is supported by operating grants and a group grant from the Canadian Institutes for Health Research, as well as by the Canadian Foundation for Innovation. P.K. is an Alberta Heritage Foundation for Medical Research (AIHS) Scientist and the Snyder Chair in Critical Care Medicine. E.K. is supported by an FP7-PEOPLE-2010-IOF grant (No. 273340) from the European Union.

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Glossary

Liver X receptors

(LXRs). Oxysterol-activated nuclear receptors that regulate cholesterol homeostasis.

M1 macrophages

Classically activated macrophages that are characterized by a pro-inflammatory interleukin-12 (IL-12)hi IL-23hi IL-10low phenotype and express inducible nitric oxide synthase (iNOS).

M2 macrophages

Alternatively activated macrophages that are characterized by an anti-inflammatory and pro-reparatory phenotype. M2 macrophages are interleukin-12 (IL-12)low IL-23low IL-10hi and express arginase 1, the mannose receptor CD206 and the IL-4 receptor α-chain.

Invariant natural killer T cells

(iNKT cells). Types of T lymphocyte that express a T cell receptor with an invariant Vα14-Jα18 chain in mice (Vα24-Jα18 in humans) paired with limited Vβ chains. iNKT cells recognize lipid antigens presented by CD1d (an atypical MHC class I-like molecule).

Pericyte

An elongated cell that is embedded within the venular basement membrane and surrounds the endothelial cells of some capillaries and venules.

α-galactosylceramide

A lipid isolated from marine sponge Agelas mauritianus that is a CD1-dependent antigen for invariant natural killer T cells.

NLRP3 inflammasome

The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome of the NOD-like receptor family is a multiprotein complex that activates caspase 1, leading to the processing of pro-interleukin-1β and pro-interleukin-18.

Intracellular matrix

(ICM). Intracellular matrix (as opposed to extracellular matrix) is present in physiological conditions exclusively inside cells in either the cytosol or nucleus.

Specialized pro-resolving mediators

Lipid mediators that are synthesized from ω-3 poly-unsaturated fatty acids (distinct from classic eicosanoids (prostaglandins and leukotrienes)) and that act in an anti-inflammatory manner.

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Kolaczkowska, E., Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 13, 159–175 (2013). https://doi.org/10.1038/nri3399

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