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Neutrophils in the activation and regulation of innate and adaptive immunity

Nature Reviews Immunology volume 11, pages 519–531 (2011)Cite this article

Subjects

Key Points

  • Neutrophils have long been viewed as short-lived effector cells of the innate immune system, with a primary role in resistance against extracellular pathogens and in acute inflammation.

  • Neutrophils express a vast repertoire of pattern recognition receptors and in response to signals undergo functional reprogramming. In addition to classical antimicrobial molecules (such as reactive oxygen intermediates), the effector repertoire of neutrophils includes an array of cytokines and chemokines, components of the humoral arm of innate immunity (such as pentraxin 3) and the formation of neutrophil extracellular traps. Thus, the participation of these 'unsung heroes' to mechanisms of innate resistance goes well beyond the production of microorganism- and tissue-damaging molecules, to include a diverse, highly regulated, customized production of cytokines and antibody-like soluble pattern recognition molecules, as well as the release of neutrophil extracellular traps.

  • Once recruited into tissues, neutrophils engage in complex bidirectional interactions with macrophages, mesenchymal stem cells, dendritic cells, natural killer cells, and B and T cells.

  • In particular, neutrophils contribute to the activation, orientation and expression of adaptive immune responses.

  • Given their role as a component of innate and adaptive responses, it is not surprising that neutrophils have emerged as important players in the pathogenesis of numerous disorders, including infection caused by intracellular pathogens, autoimmunity, chronic inflammation and cancer.

  • These new perspectives raise the issue of targeting neutrophils as a therapeutic strategy in immunopathology.

Abstract

Neutrophils have long been viewed as the final effector cells of an acute inflammatory response, with a primary role in the clearance of extracellular pathogens. However, more recent evidence has extended the functions of these cells. The newly discovered repertoire of effector molecules in the neutrophil armamentarium includes a broad array of cytokines, extracellular traps and effector molecules of the humoral arm of the innate immune system. In addition, neutrophils are involved in the activation, regulation and effector functions of innate and adaptive immune cells. Accordingly, neutrophils have a crucial role in the pathogenesis of a broad range of diseases, including infections caused by intracellular pathogens, autoimmunity, chronic inflammation and cancer.

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Figure 1: Neutrophils crosstalk with immune and non-immune cells in inflamed tissues and lymph nodes.
Figure 2: Crosstalk between neutrophils, NK cells and SLAN+ DCs.
Figure 3: Interplay between neutrophils and T cells.
Figure 4: The role of neutrophils in the resolution of inflammation.
Figure 5: Tumour-associated neutrophils.

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References

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  3. 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 

  4. Cassatella, M. A. Neutrophil-derived proteins: selling cytokines by the pound. Adv. Immunol. 73, 369–509 (1999).

    CAS  PubMed  Google Scholar 

  5. Kobayashi, S. D. & DeLeo, F. R. Role of neutrophils in innate immunity: a systems biology-level approach. Wiley Interdiscip. Rev. Syst. Biol. Med. 1, 309–333 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Pelletier, M. et al. Evidence for a cross-talk between human neutrophils and Th17 cells. Blood 115, 335–343 (2010). This paper provides the first evidence that human neutrophils and T H 17 cells, upon activation, can directly recruit each other, via specific chemokine release.

    CAS  PubMed  Google Scholar 

  7. Kotz, K. T. et al. Clinical microfluidics for neutrophil genomics and proteomics. Nature Med. 16, 1042–1047 (2010).

    CAS  PubMed  Google Scholar 

  8. Bazzoni, F. et al. Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals. Proc. Natl Acad. Sci. USA 106, 5282–5287 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009). This was the first study supporting the view that TANs can be polarized towards an 'N1' or an 'N2' phenotype, mirroring M1 and M2 macrophages.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

  11. Segal, A. W. How neutrophils kill microbes. Annu. Rev. Immunol. 23, 197–223 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  13. McDonald, B. et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330, 362–366 (2010). Taking advantage of dynamic in vivo imaging to visualize the innate immune response, this report uncovers a multistep hierarchy of directional cues that guides neutrophil localization in a mouse model of sterile liver inflammation.

    CAS  PubMed  Google Scholar 

  14. Hayashi, F., Means, T. K. & Luster, A. D. Toll-like receptors stimulate human neutrophil function. Blood 102, 2660–2669 (2003).

    CAS  PubMed  Google Scholar 

  15. Greenblatt, M. B., Aliprantis, A., Hu, B. & Glimcher, L. H. Calcineurin regulates innate antifungal immunity in neutrophils. J. Exp. Med. 207, 923–931 (2010). This paper elucidates that the increased susceptibility to fungal infections observed in patients treated with cyclosporine A, one of the most potent immunosuppressants available, is not the consequence of its broad inhibition of T cell responses but rather maps to the function of calcineurin B in neutrophils.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kerrigan, A. M. et al. CLEC-2 is a phagocytic activation receptor expressed on murine peripheral blood neutrophils. J. Immunol. 182, 4150–4157 (2009).

    CAS  PubMed  Google Scholar 

  17. Tamassia, N. et al. Activation of an immunoregulatory and antiviral gene expression program in poly(I:C)-transfected human neutrophils. J. Immunol. 181, 6563–6573 (2008).

    CAS  PubMed  Google Scholar 

  18. Clarke, T. B. et al. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nature Med. 16, 228–231 (2010).

    CAS  PubMed  Google Scholar 

  19. Scapini, P., Bazzoni, F. & Cassatella, M. A. Regulation of B-cell-activating factor (BAFF)/B lymphocyte stimulator (BLyS) expression in human neutrophils. Immunol. Lett. 116, 1–6 (2008).

    CAS  PubMed  Google Scholar 

  20. Yamada, M. et al. Interferon-γ production by neutrophils during bacterial pneumonia in mice. Am. J. Respir. Crit. Care Med. 183, 1391–1401 (2011).

    CAS  PubMed  Google Scholar 

  21. Huard, B. et al. APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa. J. Clin. Invest. 118, 2887–2895 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Gabay, C. et al. Synovial tissues concentrate secreted APRIL. Arthritis Res. Ther. 11, R144 (2009).

    PubMed  PubMed Central  Google Scholar 

  23. Roosnek, E. et al. Tumors that look for their springtime in APRIL. Crit. Rev. Oncol. Hematol. 72, 91–97 (2009).

    CAS  PubMed  Google Scholar 

  24. Chakravarti, A., Raquil, M. A., Tessier, P. & Poubelle, P. E. Surface RANKL of Toll-like receptor 4-stimulated human neutrophils activates osteoclastic bone resorption. Blood 114, 1633–1644 (2009). This paper uncovers a new biological feature of human, as well as mouse, neutrophils. These cells are important in osteoclastogenesis, through their capacity to activate osteoclastic bone resorption.

    CAS  PubMed  Google Scholar 

  25. Poubelle, P. E., Chakravarti, A., Fernandes, M. J., Doiron, K. & Marceau, A. A. Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils from patients with rheumatoid arthritis and by healthy human blood neutrophils. Arthritis Res. Ther. 9, R25 (2007).

    PubMed  PubMed Central  Google Scholar 

  26. Ethuin, F. et al. Human neutrophils produce interferon γ upon stimulation by interleukin-12. Lab. Invest. 84, 1363–1371 (2004).

    CAS  PubMed  Google Scholar 

  27. Pelletier, M., Micheletti, A. & Cassatella, M. A. Modulation of human neutrophil survival and antigen expression by activated CD4+ and CD8+ T cells. J. Leukoc. Biol. 88, 1163–1170 (2010).

    CAS  PubMed  Google Scholar 

  28. Reglier, H., Arce-Vicioso, M., Fay, M., Gougerot-Pocidalo, M. A. & Chollet-Martin, S. Lack of IL-10 and IL-13 production by human polymorphonuclear neutrophils. Cytokine 10, 192–198 (1998).

    CAS  PubMed  Google Scholar 

  29. 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).

    CAS  Google Scholar 

  30. Cassatella, M. A., Locati, M. & Mantovani, A. Never underestimate the power of a neutrophil. Immunity 31, 698–700 (2009).

    CAS  PubMed  Google Scholar 

  31. 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). A study demonstrating that, in mice, neutrophils represent a major source of IL-10.

    CAS  PubMed  Google Scholar 

  32. 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).

    CAS  PubMed  Google Scholar 

  33. Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).

    CAS  PubMed  Google Scholar 

  34. Bottazzi, B., Doni, A., Garlanda, C. & Mantovani, A. An integrated view of humoral innate immunity: pentraxins as a paradigm. Annu. Rev. Immunol. 28, 157–183 (2010).

    CAS  PubMed  Google Scholar 

  35. Jaillon, S. et al. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J. Exp. Med. 204, 793–804 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Lu, J. et al. Structural recognition and functional activation of FcγR by innate pentraxins. Nature 456, 989–992 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Moalli, F. et al. Role of complement and Fcγ receptors in the protective activity of the long pentraxin PTX3 against Aspergillus fumigatus. Blood 116, 5170–5180 (2010).

    CAS  PubMed  Google Scholar 

  38. Deban, L. et al. Regulation of leukocyte recruitment by the long pentraxin PTX3. Nature Immunol. 11, 328–334 (2010).

    CAS  Google Scholar 

  39. Cho, J. H. et al. Human peptidoglycan recognition protein S is an effector of neutrophil-mediated innate immunity. Blood 106, 2551–2558 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Dziarski, R., Platt, K. A., Gelius, E., Steiner, H. & Gupta, D. Defect in neutrophil killing and increased susceptibility to infection with nonpathogenic Gram-positive bacteria in peptidoglycan recognition protein-S (PGRP-S)-deficient mice. Blood 102, 689–697 (2003).

    CAS  PubMed  Google Scholar 

  41. Rorvig, S. et al. Ficolin-1 is present in a highly mobilizable subset of human neutrophil granules and associates with the cell surface after stimulation with fMLP. J. Leukoc. Biol. 86, 1439–1449 (2009).

    PubMed  Google Scholar 

  42. Parham, P. Innate immunity: the unsung heroes. Nature 423, 20 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  44. Brandau, S. et al. Tissue-resident mesenchymal stem cells attract peripheral blood neutrophils and enhance their inflammatory activity in response to microbial challenge. J. Leukoc. Biol. 88, 1005–1015 (2010).

    CAS  PubMed  Google Scholar 

  45. Cassatella, M. A. et al. Toll-like receptor-3-activated human mesenchymal stromal cells significantly prolong the survival and function of neutrophils. Stem Cells 29, 1001–1011 (2011).

    CAS  PubMed  Google Scholar 

  46. Bennouna, S. & Denkers, E. Y. Microbial antigen triggers rapid mobilization of TNF-α to the surface of mouse neutrophils transforming them into inducers of high-level dendritic cell TNF-α production. J. Immunol. 174, 4845–4851 (2005).

    CAS  PubMed  Google Scholar 

  47. Megiovanni, A. M. et al. Polymorphonuclear neutrophils deliver activation signals and antigenic molecules to dendritic cells: a new link between leukocytes upstream of T lymphocytes. J. Leukoc. Biol. 79, 977–988 (2006).

    CAS  PubMed  Google Scholar 

  48. van Gisbergen, K. P., Ludwig, I. S., Geijtenbeek, T. B. & van Kooyk, Y. Interactions of DC-SIGN with Mac-1 and CEACAM1 regulate contact between dendritic cells and neutrophils. FEBS Lett. 579, 6159–6168 (2005).

    CAS  PubMed  Google Scholar 

  49. van Gisbergen, K. P., Sanchez-Hernandez, M., Geijtenbeek, T. B. & van Kooyk, Y. Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between Mac-1 and DC-SIGN. J. Exp. Med. 201, 1281–1292 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Maffia, P. C. et al. Neutrophil elastase converts human immature dendritic cells into transforming growth factor-β1-secreting cells and reduces allostimulatory ability. Am. J. Pathol. 171, 928–937 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Hess, C., Sadallah, S., Hefti, A., Landmann, R. & Schifferli, J. A. Ectosomes released by human neutrophils are specialized functional units. J. Immunol. 163, 4564–4573 (1999).

    CAS  PubMed  Google Scholar 

  52. Eken, C. et al. Polymorphonuclear neutrophil-derived ectosomes interfere with the maturation of monocyte-derived dendritic cells. J. Immunol. 180, 817–824 (2008).

    CAS  PubMed  Google Scholar 

  53. Gasser, O. & Schifferli, J. A. Activated polymorphonuclear neutrophils disseminate anti-inflammatory microparticles by ectocytosis. Blood 104, 2543–2548 (2004).

    CAS  PubMed  Google Scholar 

  54. Cheong, C. et al. Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209+ dendritic cells for immune T cell areas. Cell 143, 416–429 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Costantini, C. & Cassatella, M. A. The defensive alliance between neutrophils and NK cells as a novel arm of innate immunity. J. Leukoc. Biol. 89, 221–233 (2011).

    CAS  PubMed  Google Scholar 

  56. Costantini, C. et al. Human neutrophils interact with both 6-sulfo LacNAc+ DC and NK cells to amplify NK-derived IFNγ: role of CD18, ICAM-1, and ICAM-3. Blood 117, 1677–1686 (2011). This study provides a novel perspective on the cooperative strategies used by the innate immune system in humans by showing that neutrophils can amplify the crosstalk between NK cells and a specific subset of DCs.

    CAS  PubMed  Google Scholar 

  57. MacDonald, K. P. et al. Characterization of human blood dendritic cell subsets. Blood 100, 4512–4520 (2002).

    CAS  PubMed  Google Scholar 

  58. Schakel, K. Dendritic cells — why can they help and hurt us. Exp. Dermatol. 18, 264–273 (2009).

    PubMed  Google Scholar 

  59. Costantini, C. et al. On the potential involvement of CD11d in co-stimulating the production of interferon-γ by natural killer cells upon interaction with neutrophils via intercellular adhesion molecule-3. Haematologica 28 Jun 2011 (doi:10.3324/haematol.044578).

  60. Costantini, C. et al. Neutrophil activation and survival are modulated by interaction with NK cells. Int. Immunol. 22, 827–838 (2010).

    CAS  PubMed  Google Scholar 

  61. Bhatnagar, N. et al. Cytokine-activated NK cells inhibit PMN apoptosis and preserve their functional capacity. Blood 116, 1308–1316 (2010).

    CAS  PubMed  Google Scholar 

  62. Himmel, M. E. et al. Human CD4+ FOXP3+ regulatory T cells produce CXCL8 and recruit neutrophils. Eur. J. Immunol. 41, 306–312 (2011).

    CAS  PubMed  Google Scholar 

  63. Davey, M. S. et al. Human neutrophil clearance of bacterial pathogens triggers anti-microbial γδ T cell responses in early infection. PLoS Pathog. 7, e1002040 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Abi Abdallah, D. S., Egan, C. E., Butcher, B. A. & Denkers, E. Y. Mouse neutrophils are professional antigen-presenting cells programmed to instruct Th1 and Th17 T-cell differentiation. Int. Immunol. 23, 317–326 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Beauvillain, C. et al. Neutrophils efficiently cross-prime naive T cells in vivo. Blood 110, 2965–2973 (2007).

    CAS  PubMed  Google Scholar 

  66. 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 

  67. Chtanova, T. et al. Dynamics of neutrophil migration in lymph nodes during infection. Immunity 29, 487–496 (2008). This study uses two-photon microscopy to detail the behaviour of neutrophils in lymph nodes during infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Beauvillain, C. et al. CCR7 is involved in the migration of neutrophils to lymph nodes. Blood 117, 1196–1204 (2011). This study identifies a potential mechanism involved in the migration of neutrophils to the draining lymph nodes.

    CAS  PubMed  Google Scholar 

  69. Yang, C. W., Strong, B. S., Miller, M. J. & Unanue, E. R. Neutrophils influence the level of antigen presentation during the immune response to protein antigens in adjuvants. J. Immunol. 185, 2927–2934 (2010). This study unravels a regulatory function of neutrophils in lymph nodes during an immune response.

    CAS  PubMed  Google Scholar 

  70. 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).

    CAS  Google Scholar 

  71. 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 

  72. Spite, M. et al. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature 461, 1287–1291 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Serhan, C. N. et al. Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. J. Exp. Med. 206, 15–23 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Arita, M. et al. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J. Immunol. 178, 3912–3917 (2007).

    CAS  PubMed  Google Scholar 

  75. Ariel, A. et al. Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression. Nature Immunol. 7, 1209–1216 (2006).

    CAS  Google Scholar 

  76. McKimmie, C. S. et al. Hemopoietic cell expression of the chemokine decoy receptor D6 is dynamic and regulated by GATA1. J. Immunol. 181, 3353–3363 (2008).

    CAS  PubMed  Google Scholar 

  77. Bourke, E. et al. IL-1 β scavenging by the type II IL-1 decoy receptor in human neutrophils. J. Immunol. 170, 5999–6005 (2003).

    CAS  PubMed  Google Scholar 

  78. Bazzoni, F., Tamassia, N., Rossato, M. & Cassatella, M. A. Understanding the molecular mechanisms of the multifaceted IL-10-mediated anti-inflammatory response: lessons from neutrophils. Eur. J. Immunol. 40, 2360–2368 (2010).

    CAS  PubMed  Google Scholar 

  79. Fox, S., Leitch, A. E., Duffin, R., Haslett, C. & Rossi, A. G. Neutrophil apoptosis: relevance to the innate immune response and inflammatory disease. J. Innate Immun. 2, 216–227 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Jeannin, P., Jaillon, S. & Delneste, Y. Pattern recognition receptors in the immune response against dying cells. Curr. Opin. Immunol. 20, 530–537 (2008).

    CAS  PubMed  Google Scholar 

  81. Filardy, A. A. et al. Proinflammatory clearance of apoptotic neutrophils induces an IL-12lowIL-10high regulatory phenotype in macrophages. J. Immunol. 185, 2044–2050 (2010).

    CAS  PubMed  Google Scholar 

  82. Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nature Immunol. 11, 889–896 (2010).

    CAS  Google Scholar 

  83. Bystrom, J. et al. Resolution-phase macrophages possess a unique inflammatory phenotype that is controlled by cAMP. Blood 112, 4117–4127 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Silva, M. T. When two is better than one: macrophages and neutrophils work in concert in innate immunity as complementary and cooperative partners of a myeloid phagocyte system. J. Leukoc. Biol. 87, 93–106 (2010).

    CAS  PubMed  Google Scholar 

  85. Jankowski, A., Scott, C. C. & Grinstein, S. Determinants of the phagosomal pH in neutrophils. J. Biol. Chem. 277, 6059–6066 (2002).

    CAS  PubMed  Google Scholar 

  86. Berry, M. P. et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 466, 973–977 (2010). This study highlights the importance of genome analysis in the study of pathologies. Here, a genome-wide transcriptional signature shows that neutrophils and IFN signalling are linked to the pathogenesis of tuberculosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Pedrosa, J. et al. Neutrophils play a protective nonphagocytic role in systemic Mycobacterium tuberculosis infection of mice. Infect. Immun. 68, 577–583 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Weathington, N. M. et al. A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation. Nature Med. 12, 317–323 (2006).

    CAS  PubMed  Google Scholar 

  89. Snelgrove, R. J. et al. A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science 330, 90–94 (2010). Here, the authors uncover a novel mechanism whereby cigarette smoke perpetuates neutrophil chemotaxis, with implications for new therapeutic strategies to treat debilitating lung disorders.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Alves-Filho, J. C. et al. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nature Med. 16, 708–712 (2010).

    CAS  PubMed  Google Scholar 

  91. Clark, S. R. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nature Med. 13, 463–469 (2007).

    CAS  PubMed  Google Scholar 

  92. Massberg, S. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nature Med. 16, 887–896 (2010). This study demonstrates a novel effector function of neutrophils by providing unequivocal in vivo evidence that neutrophils can activate the coagulation cascade as an antimicrobial mechanism.

    CAS  PubMed  Google Scholar 

  93. Baetta, R. & Corsini, A. Role of polymorphonuclear neutrophils in atherosclerosis: current state and future perspectives. Atherosclerosis 210, 1–13 (2010).

    CAS  PubMed  Google Scholar 

  94. Hidalgo, A. et al. Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury. Nature Med. 15, 384–391 (2009).

    CAS  PubMed  Google Scholar 

  95. Bennett, L. et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711–723 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Hakkim, A. et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc. Natl Acad. Sci. USA 107, 9813–9818 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Garcia-Romo, G. S. et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra20 (2011).

    PubMed  PubMed Central  Google Scholar 

  98. Lande, R. et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA–peptide complexes in systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra19 (2011). References 97 and 98 strengthen the concept that an interaction between neutrophils and other cell types might represent a crucial pathogenic event. Crosstalk between neutrophils and pDCs could represent the driving force for the development of SLE.

    PubMed  PubMed Central  Google Scholar 

  99. Chen, M. & Kallenberg, C. G. ANCA-associated vasculitides — advances in pathogenesis and treatment. Nature Rev. Rheumatol. 6, 653–664 (2010).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  101. Chou, R. C. et al. Lipid-cytokine-chemokine cascade drives neutrophil recruitment in a murine model of inflammatory arthritis. Immunity 33, 266–278 (2010). This study provides a detailed picture of the diverse molecules that sequentially act on neutrophils to drive their migration in a mouse model of inflammation.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Carlson, T., Kroenke, M., Rao, P., Lane, T. E. & Segal, B. The Th17–ELR+ CXC chemokine pathway is essential for the development of central nervous system autoimmune disease. J. Exp. Med. 205, 811–823 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Liu, L. et al. CXCR2-positive neutrophils are essential for cuprizone-induced demyelination: relevance to multiple sclerosis. Nature Neurosci. 13, 319–326 (2010).

    CAS  PubMed  Google Scholar 

  104. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  105. Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).

    CAS  PubMed  Google Scholar 

  106. Borrello, M. G. et al. Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. Proc. Natl Acad. Sci. USA 102, 14825–14830 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Sparmann, A. & Bar-Sagi, D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6, 447–458 (2004).

    CAS  PubMed  Google Scholar 

  108. Kuang, D. M. et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J. Hepatol. 54, 948–955 (2011).

    CAS  PubMed  Google Scholar 

  109. Wislez, M. et al. Hepatocyte growth factor production by neutrophils infiltrating bronchioloalveolar subtype pulmonary adenocarcinoma: role in tumor progression and death. Cancer Res. 63, 1405–1412 (2003).

    CAS  PubMed  Google Scholar 

  110. Charles, K. A. et al. The tumor-promoting actions of TNF-α involve TNFR1 and IL-17 in ovarian cancer in mice and humans. J. Clin. Invest. 119, 3011–3023 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Pekarek, L. A., Starr, B. A., Toledano, A. Y. & Schreiber, H. Inhibition of tumor growth by elimination of granulocytes. J. Exp. Med. 181, 435–440 (1995).

    CAS  PubMed  Google Scholar 

  112. Queen, M. M., Ryan, R. E., Holzer, R. G., Keller-Peck, C. R. & Jorcyk, C. L. Breast cancer cells stimulate neutrophils to produce oncostatin M: potential implications for tumor progression. Cancer Res. 65, 8896–8904 (2005).

    CAS  PubMed  Google Scholar 

  113. Houghton, A. M. et al. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nature Med. 16, 219–223 (2010).

    CAS  PubMed  Google Scholar 

  114. 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). This study uncovers a novel function of IFNβ, and provides a better understanding of the therapeutic effect of IFNβ treatment during the early stages of cancer development. Specifically, the authors demonstrate that, in a transplantable tumour model, endogenous IFNβ inhibits tumour angiogenesis through repression of genes encoding pro-angiogenic and homing factors in tumour-infiltrating neutrophils.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Keeley, E. C., Mehrad, B. & Strieter, R. M. CXC chemokines in cancer angiogenesis and metastases. Adv. Cancer Res. 106, 91–111 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Scapini, P. et al. CXCL1/macrophage inflammatory protein-2-induced angiogenesis in vivo is mediated by neutrophil-derived vascular endothelial growth factor-A. J. Immunol. 172, 5034–5040 (2004).

    CAS  PubMed  Google Scholar 

  117. Nozawa, H., Chiu, C. & Hanahan, D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc. Natl Acad. Sci. USA 103, 12493–12498 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Shojaei, F., Singh, M., Thompson, J. D. & Ferrara, N. Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc. Natl Acad. Sci. USA 105, 2640–2645 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Rodriguez, P. C. et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res. 69, 1553–1560 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Cuenca, A. G. et al. A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma. Mol. Med. 17, 281–292 (2011).

    CAS  PubMed  Google Scholar 

  121. Welch, D. R., Schissel, D. J., Howrey, R. P. & Aeed, P. A. Tumor-elicited polymorphonuclear cells, in contrast to “normal” circulating polymorphonuclear cells, stimulate invasive and metastatic potentials of rat mammary adenocarcinoma cells. Proc. Natl Acad. Sci. USA 86, 5859–5863 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Colombo, M. P. et al. Granulocyte colony-stimulating factor gene transfer suppresses tumorigenicity of a murine adenocarcinoma in vivo. J. Exp. Med. 173, 889–897 (1991).

    CAS  PubMed  Google Scholar 

  123. Yousefi, S., Mihalache, C., Kozlowski, E., Schmid, I. & Simon, H. U. Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps. Cell Death Differ. 16, 1438–1444 (2009).

    CAS  PubMed  Google Scholar 

  124. Urban, C. F. et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog. 5, e1000639 (2009).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Beiter, K. et al. An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Curr. Biol. 16, 401–407 (2006).

    CAS  PubMed  Google Scholar 

  127. Buchanan, J. T. et al. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr. Biol. 16, 396–400 (2006).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), special project 5 × 1000 and the European Research Council (to A.M.); S.J. is the recipient of a Mario e Valeria Rindi Fellowship from AIRC; M.A.C. is supported by Fondazione Cariverona and AIRC. We apologize to those colleagues whose work could not be cited here owing to space limitations.

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Author notes

  1. Alberto Mantovani, Marco A. Cassatella, Claudio Costantini and Sébastien Jaillon: All authors contributed equally to this work.

Authors and Affiliations

  1. Istituto Clinico Humanitas IRCCS, via Manzoni 56, Rozzano, 20089, Italy

    Alberto Mantovani & Sébastien Jaillon

  2. Department of Translational Medicine, Università degli Studi di Milano, via Manzoni 56, Rozzano, 20089, Italy

    Alberto Mantovani

  3. Department of Pathology and Diagnostics, University of Verona, Verona, 37134, Italy

    Marco A. Cassatella & Claudio Costantini

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  1. Alberto Mantovani
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Glossary

Granules

Neutrophils store an assortment of molecules in three types of granule (primary, secondary and tertiary). Primary granules are characterized by the accumulation of antimicrobial proteins and proteases, whereas secondary granules and tertiary granules are characterized by a high content of lactoferrin and gelatinase, respectively. In addition, secretory vesicles contain a reservoir of membrane-associated proteins.

Reactive oxygen intermediates

(ROI). In the context of this Review, this term refers to various reactive oxygen species, including superoxide anions produced by phagocytes via the activation of the NADPH oxidase enzymatic system, and other compounds derived from superoxide anion metabolism, such as hydrogen peroxide and hydroxyl radicals. ROI are crucial for the antimicrobial activity of neutrophils.

MicroRNAs

Single-stranded RNA molecules of approximately 21–23 nucleotides in length that are thought to regulate the expression of other genes.

N-formyl peptides

Bacteria initiate protein synthesis with N-formylmethionine, a modified form of the amino acid methionine. The only eukaryotic proteins that contain N-formylmethionine, and are therefore N-formylated, are those encoded by mitochondria.

Pattern recognition receptor

A germline-encoded receptor that recognizes unique and essential structures that are present in microorganisms, but absent from the host. In vertebrates, signalling through these receptors leads to the production of pro-inflammatory cytokines and chemokines and to the expression of co-stimulatory molecules by antigen-presenting cells.

Inflammasome

A molecular complex of several proteins — including members of the NOD-like receptor family — that upon assembly cleaves pro-interleukin-1 β (pro-IL-1β) and pro-IL-18, thereby producing the active cytokines.

Osteoclastogenesis

A process whereby haematopoietic stem cells differentiate into multinucleated osteoclasts with bone-resorbing activity.

Complement cascade

There are three independent pathways that can lead to the activation of the complement cascade. The classical pathway is activated via C1q binding to immune complexes; the alternative pathway is triggered by direct C3 activation; and the lectin pathway is initiated by the interaction of mannose-binding lectin with the surface of microorganisms.

NETosis

A form of cell death that differs from classical apoptosis and necrosis, and that occurs during the formation of neutrophil extracellular traps.

Ectosomes

Large membrane vesicles (>100nm diameter) that are secreted by budding or shedding from the plasma membrane.

SLAN

(6-sulpho LacNAc). A carbohydrate modification of P-selectin glycoprotein ligand 1 (PSGL1). SLAN is expressed by a subset of dendritic cells found in human blood and is recognized by the monoclonal antibody MDC8.

Resolvins

Lipid mediators that are induced in the resolution phase following acute inflammation. They are synthesized from the essential omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid.

Eat-me signals

Signals emitted by dying cells to facilitate their recognition and phagocytosis by neighbouring healthy cells.

Chronic obstructive pulmonary disease

(COPD). A group of diseases characterized by the pathological limitation of airflow in the airway, including chronic obstructive bronchitis and emphysema. It is most often caused by tobacco smoking, but can also be caused by other airborne irritants (such as coal dust) and occasionally by genetic abnormalities, such as α1-antitrypsin deficiency.

Antinuclear antibodies

(ANAs). Heterogeneous autoantibodies specific for one or more antigens present in the nucleus, including chromatin, nucleosomes and ribonuclear proteins. ANAs are found in association with many different autoimmune diseases.

K/BxN transgenic mouse

A mouse strain formed by crossing NOD/Lt mice with C57BL/6 KRN T cell receptor-transgenic mice in which T cells recognize a peptide from the autoantigen glucose-6-phosphate isomerase (GPI). These mice develop a form of arthritis that is mediated, and can be transferred, by circulating antibody specific for GPI.

Immunoediting

The process by which interaction of a heterogeneous population of tumour cells with the immune system generates tumour variants with reduced immunogenicity that might therefore escape from immune responses.

Angiogenesis

The development of new blood vessels from existing blood vessels. Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in granulation tissue formation. It is also a fundamental step for the growth of dormant tumours.

Myeloid-derived suppressor cells

A heterogenous collection of cells at different stages in the myeloid and monocytic differentiation pathway that have immunosuppressive functions. These cells include bona fide monocytes and neutrophils.

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Mantovani, A., Cassatella, M., Costantini, C. et al. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11, 519–531 (2011). https://doi.org/10.1038/nri3024

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