Neutrophils as emerging therapeutic targets

Abstract

Neutrophils are the most abundant circulating leukocytes, being the first line of defence against bacterial and fungal infections. However, neutrophils also contribute to tissue damage during various autoimmune and inflammatory diseases, and play important roles in cancer progression. The intimate but complex involvement of neutrophils in various diseases makes them exciting targets for therapeutic intervention but also necessitates differentiation of beneficial responses from potentially detrimental side effects. A variety of approaches to therapeutically target neutrophils have emerged, including strategies to enhance, inhibit or restore neutrophil function, with several agents entering clinical trials. However, challenges and controversies in the field remain.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Overview of neutrophil development and function.
Fig. 2: Signal transduction by neutrophil activating cell surface receptors.
Fig. 3: Neutrophils in cancer.
Fig. 4: Targeting neutrophils in diseases.

References

  1. 1.

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

  2. 2.

    Mócsai, A. Diverse novel functions of neutrophils in immunity, inflammation, and beyond. J. Exp. Med. 210, 1283–1299 (2013).

  3. 3.

    Ley, K. et al. Neutrophils: New insights and open questions. Sci. Immunol. 3, eaat4579 (2018).

  4. 4.

    Németh, T. & Mócsai, A. The role of neutrophils in autoimmune diseases. Immunol. Lett. 143, 9–19 (2012).

  5. 5.

    Coffelt, S. B., Wellenstein, M. D. & de Visser, K. E. Neutrophils in cancer: neutral no more. Nat. Rev. Cancer 16, 431–446 (2016).

  6. 6.

    Cowland, J. B. & Borregaard, N. Granulopoiesis and granules of human neutrophils. Immunol. Rev. 273, 11–28 (2016).

  7. 7.

    Zhu, Y. P. et al. Identification of an early unipotent neutrophil progenitor with pro-tumoral activity in mouse and human bone marrow. Cell Rep. 24, 2329–2341 (2018).

  8. 8.

    Gorgens, A. et al. Revision of the human hematopoietic tree: granulocyte subtypes derive from distinct hematopoietic lineages. Cell Rep. 3, 1539–1552 (2013).

  9. 9.

    Paul, F. et al. Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 163, 1663–1677 (2015).

  10. 10.

    Evrard, M. et al. Developmental analysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions. Immunity 48, 364–379 (2018).

  11. 11.

    Pillay, J. et al. In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood 116, 625–627 (2010). This article suggests that neutrophils survive for several days, much longer than previously thought.

  12. 12.

    Adrover, J. M., Nicolas-Avila, J. A. & Hidalgo, A. Aging: a temporal dimension for neutrophils. Trends Immunol. 37, 334–345 (2016).

  13. 13.

    Casanova-Acebes, M. et al. Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell 153, 1025–1035 (2013).

  14. 14.

    Zhang, D. et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015).

  15. 15.

    Scheiermann, C. et al. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity 37, 290–301 (2012).

  16. 16.

    Ella, K., Mócsai, A. & Káldi, K. Circadian regulation of neutrophils: control by a cell-autonomous clock or systemic factors? Eur. J. Clin. Invest. 48, e12965 (2018).

  17. 17.

    He, W. et al. Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues. Immunity 49, 1175–1190 e1177 (2018).

  18. 18.

    Casanova-Acebes, M. et al. Neutrophils instruct homeostatic and pathological states in naive tissues. J. Exp. Med. 215, 2778–2795 (2018).

  19. 19.

    Manz, M. G. & Boettcher, S. Emergency granulopoiesis. Nat. Rev. Immunol. 14, 302–314 (2014).

  20. 20.

    Martin, C. et al. Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 19, 583–593 (2003).

  21. 21.

    Eash, K. J., Greenbaum, A. M., Gopalan, P. K. & Link, D. C. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J. Clin. Invest. 120, 2423–2431 (2010).

  22. 22.

    Al Ustwani, O., Kurzrock, R. & Wetzler, M. Genetics on a WHIM. Br. J. Haematol. 164, 15–23 (2014).

  23. 23.

    Stark, M. A. et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285–294 (2005). This study identifies a homeostatic feedback loop for the regulation of neutrophil numbers.

  24. 24.

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

  25. 25.

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

  26. 26.

    Schmidt, S., Moser, M. & Sperandio, M. The molecular basis of leukocyte recruitment and its deficiencies. Mol. Immunol. 55, 49–58 (2013).

  27. 27.

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

  28. 28.

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

  29. 29.

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

  30. 30.

    Voisin, M. B. & Nourshargh, S. Neutrophil transmigration: emergence of an adhesive cascade within venular walls. J. Innate Immun. 5, 336–347 (2013).

  31. 31.

    Kurz, A. R. M., Catz, S. D. & Sperandio, M. Noncanonical Hippo signalling in the regulation of leukocyte function. Trends Immunol. 39, 656–669 (2018).

  32. 32.

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

  33. 33.

    Stark, K. et al. Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and ‘instruct’ them with pattern-recognition and motility programs. Nat. Immunol. 14, 41–51 (2013).

  34. 34.

    Rossaint, J. & Zarbock, A. Tissue-specific neutrophil recruitment into the lung, liver, and kidney. J. Innate Immun. 5, 348–357 (2013).

  35. 35.

    Nourshargh, S., Renshaw, S. A. & Imhof, B. A. Reverse migration of neutrophils: where, when, how, and why? Trends Immunol. 37, 273–286 (2016).

  36. 36.

    Lammermann, T. et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453, 51–55 (2008).

  37. 37.

    Németh, T. & Mócsai, A. Feedback amplification of neutrophil function. Trends Immunol. 37, 412–424 (2016).

  38. 38.

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

  39. 39.

    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). This study indicates a critical role for neutrophil signalling in the generation of the inflammatory microenvironment.

  40. 40.

    Lammermann, T. et al. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498, 371–375 (2013). This article provides a detailed analysis of the neutrophil swarming process.

  41. 41.

    Kienle, K. & Lammermann, T. Neutrophil swarming: an essential process of the neutrophil tissue response. Immunol. Rev. 273, 76–93 (2016).

  42. 42.

    Winterbourn, C. C. & Kettle, A. J. Redox reactions and microbial killing in the neutrophil phagosome. Antioxid. Redox Signal. 18, 642–660 (2013).

  43. 43.

    Stapels, D. A., Geisbrecht, B. V. & Rooijakkers, S. H. Neutrophil serine proteases in antibacterial defense. Curr. Opin. Microbiol. 23, 42–48 (2015).

  44. 44.

    Reeves, E. P. et al. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 416, 291–297 (2002). This article proposes a mechanism whereby the neutrophil NADPH oxidase enhances the activity of granule enzymes.

  45. 45.

    Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004). This is the first description of NETs.

  46. 46.

    Daniel, C. et al. Extracellular DNA traps in inflammation, injury and healing. Nat. Rev. Nephrol. 15, 559–575 (2019).

  47. 47.

    Porto, B. N. & Stein, R. T. Neutrophil extracellular traps in pulmonary diseases: Too much of a good thing? Front. Immunol. 7, 311 (2016).

  48. 48.

    Sollberger, G. et al. Gasdermin D plays a vital role in the generation of neutrophil extracellular traps. Sci. Immunol. 3, eaar6689 (2018).

  49. 49.

    Chen, K. W. et al. Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps. Sci. Immunol. 3, eaar6676 (2018).

  50. 50.

    Jimenez-Alcazar, M. et al. Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science 358, 1202–1206 (2017).

  51. 51.

    Tecchio, C. & Cassatella, M. A. Neutrophil-derived chemokines on the road to immunity. Semin. Immunol. 28, 119–128 (2016).

  52. 52.

    Weber, F. C. et al. Neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity. J. Exp. Med. 212, 15–22 (2015). This article shows a role for neutrophils in T cell priming.

  53. 53.

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

  54. 54.

    Németh, T., Futosi, K., Sitaru, C., Ruland, J. & Mócsai, A. Neutrophil-specific deletion of the CARD9 gene expression regulator suppresses autoantibody-induced inflammation in vivo. Nat. Commun. 7, 11004 (2016). This study shows that blocking gene expression changes in neutrophils attenuates in vivo inflammation.

  55. 55.

    Timár, C. I. et al. Antibacterial effect of microvesicles released from human neutrophilic granulocytes. Blood 121, 510–518 (2013). This study reveals the antimicrobial effect of neutrophil-derived extracellular vesicles.

  56. 56.

    Majumdar, R., Tavakoli Tameh, A. & Parent, C. A. Exosomes mediate LTB4 release during neutrophil chemotaxis. PLOS Biol. 14, e1002336 (2016).

  57. 57.

    Benito-Martin, A., Di Giannatale, A., Ceder, S. & Peinado, H. The new deal: a potential role for secreted vesicles in innate immunity and tumor progression. Front. Immunol. 6, 66 (2015).

  58. 58.

    Vargas, A., Roux-Dalvai, F., Droit, A. & Lavoie, J. P. Neutrophil-derived exosomes: A new mechanism contributing to airway smooth muscle remodeling. Am. J. Respir. Cell Mol. Biol. 55, 450–461 (2016).

  59. 59.

    Futosi, K. & Mócsai, A. Tyrosine kinase signaling pathways in neutrophils. Immunol. Rev. 273, 121–139 (2016).

  60. 60.

    van Rees, D. J., Szilagyi, K., Kuijpers, T. W., Matlung, H. L. & van den Berg, T. K. Immunoreceptors on neutrophils. Semin. Immunol. 28, 94–108 (2016).

  61. 61.

    Weiss, E. & Kretschmer, D. Formyl-peptide receptors in infection, inflammation, and cancer. Trends Immunol. 39, 815–829 (2018).

  62. 62.

    Saeki, K. & Yokomizo, T. Identification, signaling, and functions of LTB4 receptors. Semin. Immunol. 33, 30–36 (2017).

  63. 63.

    Sadik, C. D., Miyabe, Y., Sezin, T. & Luster, A. D. The critical role of C5a as an initiator of neutrophil-mediated autoimmune inflammation of the joint and skin. Semin. Immunol. 37, 21–29 (2018).

  64. 64.

    Wang, X. & Chen, D. Purinergic regulation of neutrophil function. Front. Immunol. 9, 399 (2018).

  65. 65.

    Bruhns, P. & Jonsson, F. Mouse and human FcR effector functions. Immunol. Rev. 268, 25–51 (2015).

  66. 66.

    Aleyd, E., Heineke, M. H. & van Egmond, M. The era of the immunoglobulin A Fc receptor FcαRI; its function and potential as target in disease. Immunol. Rev. 268, 123–138 (2015).

  67. 67.

    Mócsai, A., Ruland, J. & Tybulewicz, V. L. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat. Rev. Immunol. 10, 387–402 (2010).

  68. 68.

    Favier, B. Regulation of neutrophil functions through inhibitory receptors: an emerging paradigm in health and disease. Immunol. Rev. 273, 140–155 (2016).

  69. 69.

    Jakus, Z., Fodor, S., Abram, C. L., Lowell, C. A. & Mócsai, A. Immunoreceptor-like signaling by β2 and β3 integrins. Trends Cell Biol. 17, 493–501 (2007).

  70. 70.

    Blazek, K. et al. IFN-λ resolves inflammation via suppression of neutrophil infiltration and IL-1β production. J. Exp. Med. 212, 845–853 (2015).

  71. 71.

    Espinosa, V. et al. Type III interferon is a critical regulator of innate antifungal immunity. Sci. Immunol. 2, eaan5357 (2017).

  72. 72.

    Broggi, A., Tan, Y., Granucci, F. & Zanoni, I. IFN-λ suppresses intestinal inflammation by non-translational regulation of neutrophil function. Nat. Immunol. 18, 1084–1093 (2017).

  73. 73.

    Bakele, M. et al. Localization and functionality of the inflammasome in neutrophils. J. Biol. Chem. 289, 5320–5329 (2014).

  74. 74.

    Chen, K. W. et al. The murine neutrophil NLRP3 inflammasome is activated by soluble but not particulate or crystalline agonists. Eur. J. Immunol. 46, 1004–1010 (2016).

  75. 75.

    Finisguerra, V. et al. MET is required for the recruitment of anti-tumoural neutrophils. Nature 522, 349–353 (2015).

  76. 76.

    Glodde, N. et al. Reactive neutrophil responses dependent on the receptor tyrosine kinase c-MET limit cancer immunotherapy. Immunity 47, 789–802 e789 (2017).

  77. 77.

    Matlung, H. L., Szilagyi, K., Barclay, N. A. & van den Berg, T. K. The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer. Immunol. Rev. 276, 145–164 (2017).

  78. 78.

    McMillan, S. J. et al. Siglec-E is a negative regulator of acute pulmonary neutrophil inflammation and suppresses CD11b β2-integrin-dependent signaling. Blood 121, 2084–2094 (2013).

  79. 79.

    Azcutia, V., Parkos, C. A. & Brazil, J. C. Role of negative regulation of immune signaling pathways in neutrophil function. J. Leukoc. Biol. 103, 1029–1041 (2018).

  80. 80.

    Kobayashi, S. D., Malachowa, N. & DeLeo, F. R. Influence of microbes on neutrophil life and death. Front. Cell Infect. Microbiol. 7, 159 (2017).

  81. 81.

    Csepregi, J. Z. et al. Myeloid-specific deletion of Mcl-1 yields severely neutropenic mice that survive and breed in homozygous form. J. Immunol. 201, 3793–3803 (2018).

  82. 82.

    Greenlee-Wacker, M. C. Clearance of apoptotic neutrophils and resolution of inflammation. Immunol. Rev. 273, 357–370 (2016).

  83. 83.

    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).

  84. 84.

    Wang, J. et al. Visualizing the function and fate of neutrophils in sterile injury and repair. Science 358, 111–116 (2017).

  85. 85.

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

  86. 86.

    Honda, M. & Kubes, P. Neutrophils and neutrophil extracellular traps in the liver and gastrointestinal system. Nat. Rev. Gastroenterol. Hepatol. 15, 206–221 (2018).

  87. 87.

    Mortaz, E., Alipoor, S. D., Adcock, I. M., Mumby, S. & Koenderman, L. Update on neutrophil function in severe inflammation. Front. Immunol. 9, 2171 (2018).

  88. 88.

    Schwab, L. et al. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nat. Med. 20, 648–654 (2014).

  89. 89.

    Moutsopoulos, N. M. et al. Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss. Sci. Transl Med. 6, 229ra040 (2014).

  90. 90.

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

  91. 91.

    Jenne, C. N. et al. Neutrophils recruited to sites of infection protect from virus challenge by releasing neutrophil extracellular traps. Cell Host Microbe 13, 169–180 (2013).

  92. 92.

    Sonego, F. et al. Paradoxical roles of the neutrophil in sepsis: Protective and deleterious. Front. Immunol. 7, 155 (2016).

  93. 93.

    Hotchkiss, R. S., Monneret, G. & Payen, D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat. Rev. Immunol. 13, 862–874 (2013).

  94. 94.

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

  95. 95.

    Looney, M. R., Su, X., Van Ziffle, J. A., Lowell, C. A. & Matthay, M. A. Neutrophils and their Fcγ receptors are essential in a mouse model of transfusion-related acute lung injury. J. Clin. Invest. 116, 1615–1623 (2006).

  96. 96.

    Sercundes, M. K. et al. Targeting neutrophils to prevent Malaria-associated acute lung injury/acute respiratory distress syndrome in mice. PLOS Pathog. 12, e1006054 (2016).

  97. 97.

    Williams, A. E. & Chambers, R. C. The mercurial nature of neutrophils: still an enigma in ARDS? Am. J. Physiol. Lung Cell Mol. Physiol 306, L217–L230 (2014).

  98. 98.

    Meijer, M., Rijkers, G. T. & van Overveld, F. J. Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease. Expert Rev. Clin. Immunol. 9, 1055–1068 (2013).

  99. 99.

    Laval, J., Ralhan, A. & Hartl, D. Neutrophils in cystic fibrosis. Biol. Chem. 397, 485–496 (2016).

  100. 100.

    Panettieri, R. A. Jr. The Role of neutrophils in asthma. Immunol. Allergy Clin. North. Am. 38, 629–638 (2018).

  101. 101.

    Seys, S. F., Lokwani, R., Simpson, J. L. & Bullens, D. M. A. New insights in neutrophilic asthma. Curr. Opin. Pulm. Med. 25, 113–120 (2019).

  102. 102.

    Rennard, S. I. et al. CXCR2 antagonist MK-7123. A phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 191, 1001–1011 (2015).

  103. 103.

    Mardh, C. K. et al. Targets of neutrophil influx and weaponry: therapeutic opportunities for chronic obstructive airway disease. J. Immunol. Res. 2017, 5273201 (2017).

  104. 104.

    Krishnamoorthy, N. et al. Neutrophil cytoplasts induce TH17 differentiation and skew inflammation toward neutrophilia in severe asthma. Sci. Immunol. 3, eaao4747 (2018).

  105. 105.

    Sly, P. D. et al. Risk factors for bronchiectasis in children with cystic fibrosis. N. Engl. J. Med. 368, 1963–1970 (2013).

  106. 106.

    Painter, R. G. et al. CFTR expression in human neutrophils and the phagolysosomal chlorination defect in cystic fibrosis. Biochemistry 45, 10260–10269 (2006).

  107. 107.

    Dwyer, M. et al. Cystic fibrosis sputum DNA has NETosis characteristics and neutrophil extracellular trap release is regulated by macrophage migration-inhibitory factor. J. Innate Immun. 6, 765–779 (2014).

  108. 108.

    Soehnlein, O. Multiple roles for neutrophils in atherosclerosis. Circ. Res. 110, 875–888 (2012).

  109. 109.

    Ionita, M. G. et al. High neutrophil numbers in human carotid atherosclerotic plaques are associated with characteristics of rupture-prone lesions. Arterioscler. Thromb. Vasc. Biol. 30, 1842–1848 (2010).

  110. 110.

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

  111. 111.

    Doring, Y. et al. Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation 125, 1673–1683 (2012).

  112. 112.

    Knight, J. S. et al. Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis. Circ. Res. 114, 947–956 (2014).

  113. 113.

    Silvestre-Roig, C. et al. Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death. Nature 569, 236–240 (2019). This article describes a neutrophil-mediated mechanism for the destabilization of atherosclerotic plaques.

  114. 114.

    Nahrendorf, M. Myeloid cell contributions to cardiovascular health and disease. Nat. Med. 24, 711–720 (2018).

  115. 115.

    Eltzschig, H. K. & Eckle, T. Ischemia and reperfusion-from mechanism to translation. Nat. Med. 17, 1391–1401 (2011).

  116. 116.

    Yan, X. et al. Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction. J. Mol. Cell Cardiol. 62, 24–35 (2013).

  117. 117.

    Mizuma, A. & Yenari, M. A. Anti-inflammatory targets for the treatment of reperfusion injury in stroke. Front. Neurol. 8, 467 (2017).

  118. 118.

    Anzai, A. et al. The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes. J. Exp. Med. 214, 3293–3310 (2017).

  119. 119.

    Garcia-Prieto, J. et al. Neutrophil stunning by metoprolol reduces infarct size. Nat. Commun. 8, 14780 (2017).

  120. 120.

    Horckmans, M. et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur. Heart J. 38, 187–197 (2017).

  121. 121.

    Darbousset, R. et al. Tissue factor-positive neutrophils bind to injured endothelial wall and initiate thrombus formation. Blood 120, 2133–2143 (2012).

  122. 122.

    Kimball, A. S., Obi, A. T., Diaz, J. A. & Henke, P. K. The emerging role of NETs in venous thrombosis and immunothrombosis. Front. Immunol. 7, 236 (2016).

  123. 123.

    Doring, Y., Soehnlein, O. & Weber, C. Neutrophil extracellular traps in atherosclerosis and atherothrombosis. Circ. Res. 120, 736–743 (2017).

  124. 124.

    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). This is one of several seminal articles showing the prothrombotic effects of NETs.

  125. 125.

    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).

  126. 126.

    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). This article together with reference 125 suggests a self-perpetuating mechanism of autoimmunity against self-DNA through NET formation.

  127. 127.

    Gupta, S. & Kaplan, M. J. The role of neutrophils and NETosis in autoimmune and renal diseases. Nat. Rev. Nephrol. 12, 402–413 (2016).

  128. 128.

    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). This study reveals a critical role for neutrophils in a widely used arthritis model in mice.

  129. 129.

    Khandpur, R. et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl Med. 5, 178ra040 (2013).

  130. 130.

    Arnoux, F. et al. Peptidyl arginine deiminase immunization induces anticitrullinated protein antibodies in mice with particular MHC types. Proc. Natl Acad. Sci. USA 114, E10169–E10177 (2017).

  131. 131.

    So, A. K. & Martinon, F. Inflammation in gout: mechanisms and therapeutic targets. Nat. Rev. Rheumatol. 13, 639–647 (2017).

  132. 132.

    Schauer, C. et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat. Med. 20, 511–517 (2014). This article proposes an anti-inflammatory rather than proinflammatory nature of aggregated NETs.

  133. 133.

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

  134. 134.

    Katayama, H. Development of psoriasis by continuous neutrophil infiltration into the epidermis. Exp. Dermatol. 27, 1084–1091 (2018).

  135. 135.

    Toichi, E., Tachibana, T. & Furukawa, F. Rapid improvement of psoriasis vulgaris during drug-induced agranulocytosis. J. Am. Acad. Dermatol. 43, 391–395 (2000).

  136. 136.

    Szilveszter, K. P., Németh, T. & Mócsai, A. Tyrosine kinases in autoimmune and inflammatory skin diseases. Front. Immunol. 10, 1862 (2019).

  137. 137.

    Furue, K., Ito, T. & Furue, M. Differential efficacy of biologic treatments targeting the TNF-α/IL-23/IL-17 axis in psoriasis and psoriatic arthritis. Cytokine 111, 182–188 (2018).

  138. 138.

    Sitaru, C., Kromminga, A., Hashimoto, T., Brocker, E. B. & Zillikens, D. Autoantibodies to type VII collagen mediate Fcγ-dependent neutrophil activation and induce dermal-epidermal separation in cryosections of human skin. Am. J. Pathol. 161, 301–311 (2002).

  139. 139.

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

  140. 140.

    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 article identifies two functionally different subsets of tumour-associated neutrophils.

  141. 141.

    Templeton, A. J. et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J. Natl Cancer Inst. 106, dju124 (2014).

  142. 142.

    Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).

  143. 143.

    Cedervall, J., Zhang, Y. & Olsson, A. K. Tumor-induced NETosis as a risk factor for metastasis and organ failure. Cancer Res. 76, 4311–4315 (2016).

  144. 144.

    Wolach, O. et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci. Transl Med. 10, eaan8292 (2018).

  145. 145.

    Treffers, L. W., Hiemstra, I. H., Kuijpers, T. W., van den Berg, T. K. & Matlung, H. L. Neutrophils in cancer. Immunol. Rev. 273, 312–328 (2016).

  146. 146.

    Moses, K. & Brandau, S. Human neutrophils: their role in cancer and relation to myeloid-derived suppressor cells. Semin. Immunol. 28, 187–196 (2016).

  147. 147.

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

  148. 148.

    Engblom, C. et al. Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Science 358, eaal5081 (2017).

  149. 149.

    Coffelt, S. B. et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015).

  150. 150.

    Steele, C. W. et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell 29, 832–845 (2016).

  151. 151.

    Acharyya, S. et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165–178 (2012).

  152. 152.

    Wculek, S. K. & Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413–417 (2015).

  153. 153.

    Park, J. et al. Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps. Sci. Transl Med. 8, 361ra138 (2016).

  154. 154.

    Liu, Y. et al. Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell 30, 243–256 (2016).

  155. 155.

    Albrengues, J. et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science 361, eaao4227 (2018).

  156. 156.

    Granot, Z. et al. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20, 300–314 (2011).

  157. 157.

    Blaisdell, A. et al. Neutrophils oppose uterine epithelial carcinogenesis via debridement of hypoxic tumor cells. Cancer Cell 28, 785–799 (2015).

  158. 158.

    Eruslanov, E. B. et al. Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer. J. Clin. Invest. 124, 5466–5480 (2014).

  159. 159.

    Singhal, S. et al. Origin and role of a subset of tumor-associated neutrophils with antigen-presenting cell features in early-stage human lung cancer. Cancer Cell 30, 120–135 (2016).

  160. 160.

    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).

  161. 161.

    Jorch, S. K. & Kubes, P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat. Med. 23, 279–287 (2017).

  162. 162.

    Veglia, F., Perego, M. & Gabrilovich, D. Myeloid-derived suppressor cells coming of age. Nat. Immunol. 19, 108–119 (2018).

  163. 163.

    Sagiv, J. Y. et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 10, 562–573 (2015).

  164. 164.

    Patel, S. et al. Unique pattern of neutrophil migration and function during tumor progression. Nat. Immunol. 19, 1236–1247 (2018).

  165. 165.

    Veglia, F. et al. Fatty acid transport protein 2 reprograms neutrophils in cancer. Nature 569, 73–78 (2019).

  166. 166.

    Naegele, M. et al. Neutrophils in multiple sclerosis are characterized by a primed phenotype. J. Neuroimmunol. 242, 60–71 (2012).

  167. 167.

    Aube, B. et al. Neutrophils mediate blood-spinal cord barrier disruption in demyelinating neuroinflammatory diseases. J. Immunol. 193, 2438–2454 (2014).

  168. 168.

    Woodberry, T., Bouffler, S. E., Wilson, A. S., Buckland, R. L. & Brustle, A. The emerging role of neutrophil granulocytes in multiple sclerosis. J. Clin. Med. 7, E511 (2018).

  169. 169.

    Caravagna, C. et al. Diversity of innate immune cell subsets across spatial and temporal scales in an EAE mouse model. Sci. Rep. 8, 5146 (2018).

  170. 170.

    Stock, A. J., Kasus-Jacobi, A. & Pereira, H. A. The role of neutrophil granule proteins in neuroinflammation and Alzheimer’s disease. J. Neuroinflammation 15, 240 (2018).

  171. 171.

    Baik, S. H. et al. Migration of neutrophils targeting amyloid plaques in Alzheimer’s disease mouse model. Neurobiol. Aging 35, 1286–1292 (2014).

  172. 172.

    Zenaro, E. et al. Neutrophils promote Alzheimer’s disease-like pathology and cognitive decline via LFA-1 integrin. Nat. Med. 21, 880–886 (2015).

  173. 173.

    Tseng, C. W. & Liu, G. Y. Expanding roles of neutrophils in aging hosts. Curr. Opin. Immunol. 29, 43–48 (2014).

  174. 174.

    Qian, F. et al. Reduced bioenergetics and toll-like receptor 1 function in human polymorphonuclear leukocytes in aging. Aging 6, 131–139 (2014).

  175. 175.

    Sapey, E. et al. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood 123, 239–248 (2014).

  176. 176.

    Drew, W., Wilson, D. V. & Sapey, E. Inflammation and neutrophil immunosenescence in health and disease: Targeted treatments to improve clinical outcomes in the elderly. Exp. Gerontol. 105, 70–77 (2018).

  177. 177.

    Martinod, K. et al. Peptidylarginine deiminase 4 promotes age-related organ fibrosis. J. Exp. Med. 214, 439–458 (2017).

  178. 178.

    Dale, D. C. et al. A systematic literature review of the efficacy, effectiveness, and safety of filgrastim. Support Care Cancer 26, 7–20 (2018).

  179. 179.

    Bilgin, Y. M. & de Greef, G. E. Plerixafor for stem cell mobilization: the current status. Curr. Opin. Hematol. 23, 67–71 (2016).

  180. 180.

    Teixido, J., Martinez-Moreno, M., Diaz-Martinez, M. & Sevilla-Movilla, S. The good and bad faces of the CXCR4 chemokine receptor. Int. J. Biochem. Cell Biol. 95, 121–131 (2018).

  181. 181.

    Scala, S. Molecular pathways: targeting the CXCR4–CXCL12 axis—untapped potential in the tumor microenvironment. Clin. Cancer Res. 21, 4278–4285 (2015).

  182. 182.

    Wardle, D. J. et al. Effective caspase inhibition blocks neutrophil apoptosis and reveals Mcl-1 as both a regulator and a target of neutrophil caspase activation. PLOS ONE 6, e15768 (2011).

  183. 183.

    Lichtner, M. et al. HIV protease inhibitor therapy reverses neutrophil apoptosis in AIDS patients by direct calpain inhibition. Apoptosis 11, 781–787 (2006).

  184. 184.

    Albanesi, M. et al. Neutrophils mediate antibody-induced antitumor effects in mice. Blood 122, 3160–3164 (2013).

  185. 185.

    Heemskerk, N. & van Egmond, M. Monoclonal antibody-mediated killing of tumour cells by neutrophils. Eur. J. Clin. Invest. 48, e12962 (2018).

  186. 186.

    Matlung, H. L. et al. Neutrophils kill antibody-opsonized cancer cells by trogoptosis. Cell Rep. 23, 3946–3959 e3946 (2018).

  187. 187.

    Alves-Filho, J. C. et al. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat. Med. 16, 708–712 (2010). This study proposes a mechanism to restore normal neutrophil function in sepsis.

  188. 188.

    Reshetnikov, V. et al. Chemical tools for targeted amplification of reactive oxygen species in neutrophils. Front. Immunol. 9, 1827 (2018).

  189. 189.

    Cornish, A. L., Campbell, I. K., McKenzie, B. S., Chatfield, S. & Wicks, I. P. G-CSF and GM-CSF as therapeutic targets in rheumatoid arthritis. Nat. Rev. Rheumatol. 5, 554–559 (2009).

  190. 190.

    Campbell, I. K. et al. Therapeutic targeting of the G-CSF receptor reduces neutrophil trafficking and joint inflammation in antibody-mediated inflammatory arthritis. J. Immunol. 197, 4392–4402 (2016).

  191. 191.

    Lee, M. C. et al. G-CSF receptor blockade ameliorates arthritic pain and disease. J. Immunol. 198, 3565–3575 (2017).

  192. 192.

    Gaffen, S. L., Jain, R., Garg, A. V. & Cua, D. J. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat. Rev. Immunol. 14, 585–600 (2014).

  193. 193.

    van Vollenhoven, R. F. et al. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet 392, 1330–1339 (2018).

  194. 194.

    Rossi, A. G. et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat. Med. 12, 1056–1064 (2006). This study showes that CDK inhibitors promote neutrophil apoptosis.

  195. 195.

    Dzhagalov, I., St John, A. & He, Y. W. The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages. Blood 109, 1620–1626 (2007). Together with reference 81, this article shows a critical role for MCL1 in neutrophil survival in vivo.

  196. 196.

    Jonsson, H., Allen, P. & Peng, S. L. Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis. Nat. Med. 11, 666–671 (2005).

  197. 197.

    Serhan, C. N. & Levy, B. D. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J. Clin. Invest. 128, 2657–2669 (2018).

  198. 198.

    Marteyn, B. S., Burgel, P. R., Meijer, L. & Witko-Sarsat, V. Harnessing neutrophil survival mechanisms during chronic infection by Pseudomonas aeruginosa: novel therapeutic targets to dampen inflammation in cystic fibrosis. Front. Cell Infect. Microbiol. 7, 243 (2017).

  199. 199.

    Daley, J. M., Thomay, A. A., Connolly, M. D., Reichner, J. S. & Albina, J. E. Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J. Leukoc. Biol. 83, 64–70 (2008).

  200. 200.

    Ohara, M. et al. Granulocytapheresis in the treatment of patients with rheumatoid arthritis. Artif. Organs 21, 989–994 (1997).

  201. 201.

    Kamimura, K. et al. Granulocytapheresis for the treatment of severe alcoholic hepatitis: a case series and literature review. Dig. Dis. Sci. 59, 482–488 (2014).

  202. 202.

    Sacco, R. et al. Granulocytapheresis in steroid-dependent and steroid-resistant patients with inflammatory bowel disease: a prospective observational study. J. Crohns Colitis 7, e692–e697 (2013).

  203. 203.

    Mitroulis, I. et al. Leukocyte integrins: role in leukocyte recruitment and as therapeutic targets in inflammatory disease. Pharmacol. Ther. 147, 123–135 (2015).

  204. 204.

    Ley, K., Rivera-Nieves, J., Sandborn, W. J. & Shattil, S. Integrin-based therapeutics: biological basis, clinical use and new drugs. Nat. Rev. Drug Discov. 15, 173–183 (2016).

  205. 205.

    Enlimomab Acute Stroke Trial Ivestigators. Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology 57, 1428–1434 (2001).

  206. 206.

    Sperandio, M., Gleissner, C. A. & Ley, K. Glycosylation in immune cell trafficking. Immunol. Rev. 230, 97–113 (2009).

  207. 207.

    Avila, P. C. et al. Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses. Clin. Exp. Allergy 34, 77–84 (2004).

  208. 208.

    Schon, M. P., Zollner, T. M. & Boehncke, W. H. The molecular basis of lymphocyte recruitment to the skin: clues for pathogenesis and selective therapies of inflammatory disorders. J. Invest. Dermatol. 121, 951–962 (2003).

  209. 209.

    Kogan, T. P. et al. Novel synthetic inhibitors of selectin-mediated cell adhesion: synthesis of 1,6-bis[3-(3-carboxymethylphenyl)-4-(2-α-d-mannopyranosyloxy)phenyl]hexane (TBC1269). J. Med. Chem. 41, 1099–1111 (1998).

  210. 210.

    Chang, J. et al. GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice. Blood 116, 1779–1786 (2010).

  211. 211.

    Telen, M. J. et al. Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use. Blood 125, 2656–2664 (2015).

  212. 212.

    Stillie, R., Farooq, S. M., Gordon, J. R. & Stadnyk, A. W. The functional significance behind expressing two IL-8 receptor types on PMN. J. Leukoc. Biol. 86, 529–543 (2009).

  213. 213.

    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).

  214. 214.

    O’Byrne, P. M. et al. Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. Lancet Respir. Med. 4, 797–806 (2016).

  215. 215.

    Khanam, A. et al. Blockade of neutrophil’s chemokine receptors CXCR1/2 abrogate liver damage in acute-on-chronic liver failure. Front. Immunol. 8, 464 (2017).

  216. 216.

    Goldberg, G. L. et al. G-CSF and neutrophils are nonredundant mediators of murine experimental autoimmune uveoretinitis. Am. J. Pathol. 186, 172–184 (2016).

  217. 217.

    Citro, A. et al. CXCR1/2 inhibition blocks and reverses type 1 diabetes in mice. Diabetes 64, 1329–1340 (2015).

  218. 218.

    Pawlick, R. L. et al. Reparixin, a CXCR1/2 inhibitor in islet allotransplantation. Islets 8, 115–124 (2016).

  219. 219.

    Wigerblad, G. et al. Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. Ann. Rheum. Dis. 75, 730–738 (2016).

  220. 220.

    Coelho, F. M. et al. The chemokine receptors CXCR1/CXCR2 modulate antigen-induced arthritis by regulating adhesion of neutrophils to the synovial microvasculature. Arthritis Rheum. 58, 2329–2337 (2008).

  221. 221.

    Ocana, A., Nieto-Jimenez, C., Pandiella, A. & Templeton, A. J. Neutrophils in cancer: prognostic role and therapeutic strategies. Mol. Cancer 16, 137 (2017).

  222. 222.

    Winter, C. et al. Chrono-pharmacological targeting of the CCL2-CCR2 axis ameliorates atherosclerosis. Cell Metab. 28, 175–182 (2018).

  223. 223.

    Kallenberg, C. G. & Heeringa, P. Complement system activation in ANCA vasculitis: a translational success story? Mol. Immunol. 68, 53–56 (2015).

  224. 224.

    Manenti, L., Urban, M. L., Maritati, F., Galetti, M. & Vaglio, A. Complement blockade in ANCA-associated vasculitis: an index case, current concepts and future perspectives. Intern. Emerg. Med. 12, 727–731 (2017).

  225. 225.

    Xiao, H. et al. C5a receptor (CD88) blockade protects against MPO-ANCA GN. J. Am. Soc. Nephrol. 25, 225–231 (2014).

  226. 226.

    Jayne, D. R. W. et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J. Am. Soc. Nephrol. 28, 2756–2767 (2017).

  227. 227.

    Haeggstrom, J. Z. Leukotriene biosynthetic enzymes as therapeutic targets. J. Clin. Invest. 128, 2680–2690 (2018).

  228. 228.

    Li, P. et al. LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. Nat. Med. 21, 239–247 (2015).

  229. 229.

    Lee, E. K. S. et al. Leukotriene B4-mediated neutrophil recruitment causes pulmonary capillaritis during lethal fungal sepsis. Cell Host Microbe 23, 121–133 (2018).

  230. 230.

    Miyabe, Y., Miyabe, C. & Luster, A. D. LTB4 and BLT1 in inflammatory arthritis. Semin. Immunol. 33, 52–57 (2017).

  231. 231.

    Bhatt, L., Roinestad, K., Van, T. & Springman, E. B. Recent advances in clinical development of leukotriene B4 pathway drugs. Semin. Immunol. 33, 65–73 (2017).

  232. 232.

    Snelgrove, R. J. et al. A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science 330, 90–94 (2010).

  233. 233.

    O’Shea, J. J. et al. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu. Rev. Med. 66, 311–328 (2015).

  234. 234.

    Genovese, M. C. et al. Baricitinib in patients with refractory rheumatoid arthritis. N. Engl. J. Med. 374, 1243–1252 (2016).

  235. 235.

    Westhovens, R. et al. Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). Ann. Rheum. Dis. 76, 998–1008 (2017).

  236. 236.

    Strand, V. et al. Analysis of early neutropenia, clinical response, and serious infection events in patients receiving tofacitinib for rheumatoid arthritis. Arthritis Rheumatol. 66, S1086–S1087 (2014).

  237. 237.

    Mócsai, A., Zhou, M., Meng, F., Tybulewicz, V. L. & Lowell, C. A. Syk is required for integrin signaling in neutrophils. Immunity 16, 547–558 (2002).

  238. 238.

    Elliott, E. R. et al. Deletion of Syk in neutrophils prevents immune complex arthritis. J. Immunol. 187, 4319–4330 (2011).

  239. 239.

    Németh, T. et al. Lineage-specific analysis of Syk function in autoantibody-induced arthritis. Front. Immunol. 9, 555 (2018). This article together with reference 238 shows that neutrophil-specific deletion of SYK abrogates autoantibody-induced arthritis in mice.

  240. 240.

    Davis, M. I. et al. Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol. 29, 1046–1051 (2011).

  241. 241.

    Bartaula-Brevik, S., Lindstad Brattas, M. K., Tvedt, T. H. A., Reikvam, H. & Bruserud, O. Splenic tyrosine kinase (SYK) inhibitors and their possible use in acute myeloid leukemia. Expert. Opin. Investig. Drugs 27, 377–387 (2018).

  242. 242.

    Norman, P. Investigational Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Expert. Opin. Investig. Drugs 25, 891–899 (2016).

  243. 243.

    Volmering, S., Block, H., Boras, M., Lowell, C. A. & Zarbock, A. The neutrophil Btk signalosome regulates integrin activation during sterile inflammation. Immunity 44, 73–87 (2016).

  244. 244.

    Ito, M. et al. Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nat. Commun. 6, 7360 (2015).

  245. 245.

    Krupa, A. et al. Silencing Bruton’s tyrosine kinase in alveolar neutrophils protects mice from LPS/immune complex-induced acute lung injury. Am. J. Physiol. Lung Cell Mol. Physiol 307, L435–L448 (2014).

  246. 246.

    Schett, G., Sloan, V. S., Stevens, R. M. & Schafer, P. Apremilast: a novel PDE4 inhibitor in the treatment of autoimmune and inflammatory diseases. Ther. Adv. Musculoskelet. Dis. 2, 271–278 (2010).

  247. 247.

    Ogawa, E., Sato, Y., Minagawa, A. & Okuyama, R. Pathogenesis of psoriasis and development of treatment. J. Dermatol. 45, 264–272 (2018).

  248. 248.

    Lowell, C. A. & Berton, G. Resistance to endotoxic shock and reduced neutrophil migration in mice deficient for the Src-family kinases Hck and Fgr. Proc. Natl Acad. Sci. USA 95, 7580–7584 (1998).

  249. 249.

    Mócsai, A., Ligeti, E., Lowell, C. A. & Berton, G. Adhesion-dependent degranulation of neutrophils requires the Src family kinases Fgr and Hck. J. Immunol. 162, 1120–1126 (1999).

  250. 250.

    Mócsai, A. et al. Kinase pathways in chemoattractant-induced degranulation of neutrophils: The role of p38 mitogen-activated protein kinase activated by Src family kinases. J. Immunol. 164, 4321–4331 (2000).

  251. 251.

    Futosi, K. et al. Dasatinib inhibits proinflammatory functions of mature human neutrophils. Blood 119, 4981–4991 (2012).

  252. 252.

    Oliveira, G. P. et al. The effects of dasatinib in experimental acute respiratory distress syndrome depend on dose and etiology. Cell Physiol. Biochem. 36, 1644–1658 (2015).

  253. 253.

    Goncalves-de-Albuquerque, C. F. et al. The yin and yang of tyrosine kinase inhibition during experimental polymicrobial sepsis. Front. Immunol. 9, 901 (2018).

  254. 254.

    Koss, H., Bunney, T. D., Behjati, S. & Katan, M. Dysfunction of phospholipase Cγ in immune disorders and cancer. Trends Biochem. Sci. 39, 603–611 (2014).

  255. 255.

    Jakus, Z., Simon, E., Frommhold, D., Sperandio, M. & Mócsai, A. Critical role of phospholipase Cγ2 in integrin and Fc receptor-mediated neutrophil functions and the effector phase of autoimmune arthritis. J. Exp. Med. 206, 577–593 (2009).

  256. 256.

    Graham, D. B. et al. Neutrophil-mediated oxidative burst and host defense are controlled by a Vav-PLCγ2 signaling axis in mice. J. Clin. Invest. 117, 3445–3452 (2007).

  257. 257.

    Cremasco, V., Graham, D. B., Novack, D. V., Swat, W. & Faccio, R. Vav/phospholipase Cγ2-mediated control of a neutrophil-dependent murine model of rheumatoid arthritis. Arthritis Rheum. 58, 2712–2722 (2008).

  258. 258.

    De Silva, D. M. et al. Targeting the hepatocyte growth factor/Met pathway in cancer. Biochem. Soc. Trans. 45, 855–870 (2017).

  259. 259.

    Camps, M. et al. Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat. Med. 11, 936–943 (2005).

  260. 260.

    Kulkarni, S. et al. PI3Kβ plays a critical role in neutrophil activation by immune complexes. Sci. Signal. 4, ra23 (2011).

  261. 261.

    Ittner, A. et al. Regulation of PTEN activity by p38δ-PKD1 signaling in neutrophils confers inflammatory responses in the lung. J. Exp. Med. 209, 2229–2246 (2012).

  262. 262.

    Gonzalez-Teran, B. et al. p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration. EMBO J. 35, 536–552 (2016).

  263. 263.

    Norman, P. Investigational p38 inhibitors for the treatment of chronic obstructive pulmonary disease. Expert. Opin. Investig. Drugs 24, 383–392 (2015).

  264. 264.

    Wright, H. L., Moots, R. J., Bucknall, R. C. & Edwards, S. W. Neutrophil function in inflammation and inflammatory diseases. Rheumatology 49, 1618–1631 (2010).

  265. 265.

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

  266. 266.

    Spence, S. et al. Targeting Siglecs with a sialic acid-decorated nanoparticle abrogates inflammation. Sci. Transl Med. 7, 303ra140 (2015).

  267. 267.

    Polverino, E., Rosales-Mayor, E., Dale, G. E., Dembowsky, K. & Torres, A. The role of neutrophil elastase inhibitors in lung diseases. Chest 152, 249–262 (2017).

  268. 268.

    Colom, B. et al. Leukotriene B4-neutrophil elastase axis drives neutrophil reverse transendothelial cell migration in vivo. Immunity 42, 1075–1086 (2015).

  269. 269.

    Iwata, K. et al. Effect of neutrophil elastase inhibitor (sivelestat sodium) in the treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): a systematic review and meta-analysis. Intern. Med. 49, 2423–2432 (2010).

  270. 270.

    Stockley, R. et al. Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis. Respir. Med. 107, 524–533 (2013).

  271. 271.

    Korkmaz, B., Kellenberger, C., Viaud-Massuard, M. C. & Gauthier, F. Selective inhibitors of human neutrophil proteinase 3. Curr. Pharm. Des. 19, 966–976 (2013).

  272. 272.

    Yabluchanskiy, A., Ma, Y., Iyer, R. P., Hall, M. E. & Lindsey, M. L. Matrix metalloproteinase-9: many shades of function in cardiovascular disease. Physiology 28, 391–403 (2013).

  273. 273.

    Marshall, D. C. et al. Selective allosteric inhibition of MMP9 is efficacious in preclinical models of ulcerative colitis and colorectal cancer. PLOS ONE 10, e0127063 (2015).

  274. 274.

    Sandborn, W. J. et al. Andecaliximab [anti-matrix metalloproteinase-9] induction therapy for ulcerative colitis: A randomised, double-blind, placebo-controlled, phase 2/3 study in patients with moderate to severe disease. J. Crohns Colitis 12, 1021–1029 (2018).

  275. 275.

    Schreiber, S. et al. A phase 2, randomized, placebo-controlled study evaluating matrix metalloproteinase-9 inhibitor, andecaliximab, in patients with moderately to severely active Crohn’s disease. J. Crohns Colitis 12, 1014–1020 (2018).

  276. 276.

    Shah, M. A. et al. Andecaliximab/GS-5745 alone and combined with mFOLFOX6 in advanced gastric and gastroesophageal junction adenocarcinoma: results from a phase I study. Clin. Cancer Res. 24, 3829–3837 (2018).

  277. 277.

    Metzler, K. D. et al. Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity. Blood 117, 953–959 (2011).

  278. 278.

    Zheng, W. et al. PF-1355, a mechanism-based myeloperoxidase inhibitor, prevents immune complex vasculitis and anti-glomerular basement membrane glomerulonephritis. J. Pharmacol. Exp. Ther. 353, 288–298 (2015).

  279. 279.

    Apel, F., Zychlinsky, A. & Kenny, E. F. The role of neutrophil extracellular traps in rheumatic diseases. Nat. Rev. Rheumatol. 14, 467–475 (2018).

  280. 280.

    Papayannopoulos, V., Metzler, K. D., Hakkim, A. & Zychlinsky, A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J. Cell Biol. 191, 677–691 (2010).

  281. 281.

    Bronze-da-Rocha, E. & Santos-Silva, A. Neutrophil elastase inhibitors and chronic kidney disease. Int. J. Biol. Sci. 14, 1343–1360 (2018).

  282. 282.

    Li, P. et al. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J. Exp. Med. 207, 1853–1862 (2010).

  283. 283.

    Lewis, H. D. et al. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nat. Chem. Biol. 11, 189–191 (2015).

  284. 284.

    Koushik, S. et al. PAD4: pathophysiology, current therapeutics and future perspective in rheumatoid arthritis. Expert. Opin. Ther. Targets 21, 433–447 (2017).

  285. 285.

    Knight, J. S. et al. Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J. Clin. Invest. 123, 2981–2993 (2013).

  286. 286.

    Knight, J. S. et al. Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. Ann. Rheum. Dis. 74, 2199–2206 (2015). This article together with reference 285 reports beneficial effects of PAD4 inhibition in lupus.

  287. 287.

    Martinod, K. et al. PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock. Blood 125, 1948–1956 (2015).

  288. 288.

    Raup-Konsavage, W. M. et al. Neutrophil peptidyl arginine deiminase-4 has a pivotal role in ischemia/reperfusion-induced acute kidney injury. Kidney Int. 93, 365–374 (2018).

  289. 289.

    Gordon, R. A. et al. Lupus and proliferative nephritis are PAD4 independent in murine models. JCI Insight 2, 92926 (2017).

  290. 290.

    Brill, A. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J. Thromb. Haemost. 10, 136–144 (2012).

  291. 291.

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

  292. 292.

    Thomas, G. M. et al. Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice. Blood 119, 6335–6343 (2012).

  293. 293.

    Cools-Lartigue, J. et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Invest. 123, 3446–3458 (2013).

  294. 294.

    Rathkey, J. K. et al. Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Sci. Immunol. 3, eaat2738 (2018).

  295. 295.

    Pruenster, M., Vogl, T., Roth, J. & Sperandio, M. S100A8/A9: from basic science to clinical application. Pharmacol. Ther. 167, 120–131 (2016).

  296. 296.

    Gurol, T., Zhou, W. & Deng, Q. MicroRNAs in neutrophils: potential next generation therapeutics for inflammatory ailments. Immunol. Rev. 273, 29–47 (2016).

  297. 297.

    Goldberg, E. L. et al. β-hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Rep. 18, 2077–2087 (2017).

  298. 298.

    Sonego, F., Alves-Filho, J. C. & Cunha, F. Q. Targeting neutrophils in sepsis. Expert. Rev. Clin. Immunol. 10, 1019–1028 (2014).

  299. 299.

    Summers, C. et al. Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome. Thorax 69, 623–629 (2014).

  300. 300.

    Condamine, T. et al. Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci. Immunol. 1, aaf8943 (2016).

  301. 301.

    Mohamed, E., Cao, Y. & Rodriguez, P. C. Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy. Cancer Immunol. Immunother. 66, 1069–1078 (2017).

  302. 302.

    Fleming, V. et al. Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression. Front. Immunol. 9, 398 (2018).

  303. 303.

    Zhao, X. et al. Neutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage. Nat. Commun. 8, 602 (2017).

  304. 304.

    Mócsai, A. et al. The immunomodulatory adapter proteins DAP12 and Fc receptor γ-chain (FcRγ) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc. Natl Acad. Sci. USA 101, 6158–6163 (2004).

  305. 305.

    Fodor, S., Jakus, Z. & Mócsai, A. ITAM-based signaling beyond the adaptive immune response. Immunol. Lett. 104, 29–37 (2006).

  306. 306.

    Mócsai, A. et al. Integrin signaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nat. Immunol. 7, 1326–1333 (2006).

  307. 307.

    Haddy, T. B., Rana, S. R. & Castro, O. Benign ethnic neutropenia: what is a normal absolute neutrophil count? J. Lab. Clin. Med. 133, 15–22 (1999).

  308. 308.

    De Benedetti, F. et al. Neutropenia with tocilizumab treatment is not associated with increased infection risk in patients with polyarticular-course juvenile idiopathic arthritis. Arthritis. Rheumatol. 66, S67–S68 (2014).

  309. 309.

    Benedetti, F. et al. Neutropenia with tocilizumab treatment is not associated with increased infection risk in patients with systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 66, S23–S24 (2014).

  310. 310.

    Lok, L. et al. Neutrophil function and survival unaffected in healthy subjects following single administration of tocilizumab. Arthritis Rheumatol. 67, 2 (2015).

  311. 311.

    Shovman, O., Shoenfeld, Y. & Langevitz, P. Tocilizumab-induced neutropenia in rheumatoid arthritis patients with previous history of neutropenia: case series and review of literature. Immunol. Res. 61, 164–168 (2015).

  312. 312.

    Pereira, S., Zhou, M., Mócsai, A. & Lowell, C. Resting murine neutrophils express functional α4 integrins that signal through Src family kinases. J. Immunol. 166, 4115–4123 (2001).

  313. 313.

    Hirahashi, J. et al. Mac-1 signaling via Src-family and Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy. Immunity 25, 271–283 (2006).

  314. 314.

    Jakus, Z., Simon, E., Balázs, B. & Mócsai, A. Genetic deficiency of Syk protects mice from autoantibody-induced arthritis. Arthritis Rheum. 62, 1899–1910 (2010).

  315. 315.

    Németh, T., Virtic, O., Sitaru, C. & Mócsai, A. The Syk tyrosine kinase is required for skin inflammation in an in vivo mouse model of epidermolysis bullosa acquisita. J. Invest. Dermatol. 137, 2131–2139 (2017).

  316. 316.

    Van Ziffle, J. A. & Lowell, C. A. Neutrophil-specific deletion of Syk kinase results in reduced host defense to bacterial infection. Blood 114, 4871–4882 (2009).

  317. 317.

    Newbrough, S. A. et al. SLP-76 regulates Fcγ receptor and integrin signaling in neutrophils. Immunity 19, 761–769 (2003).

  318. 318.

    Clemens, R. A. et al. Loss of SLP-76 expression within myeloid cells confers resistance to neutrophil-mediated tissue damage while maintaining effective bacterial killing. J. Immunol. 178, 4606–4614 (2007).

  319. 319.

    Lenox, L. E. et al. Mutation of tyrosine 145 of lymphocyte cytosolic protein 2 protects mice from anaphylaxis and arthritis. J. Allergy Clin. Immunol. 124, 1088–1098 (2009).

  320. 320.

    Willis, V. C. et al. Protein arginine deiminase 4 inhibition is sufficient for the amelioration of collagen-induced arthritis. Clin. Exp. Immunol. 188, 263–274 (2017).

  321. 321.

    Wolf, D. et al. A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense. Nat. Commun. 9, 525 (2018).

  322. 322.

    Deniset, J. F. & Kubes, P. Neutrophil heterogeneity: bona fide subsets or polarization states? J. Leukoc. Biol. 103, 829–838 (2018).

  323. 323.

    Chu, D., Gao, J. & Wang, Z. Neutrophil-mediated delivery of therapeutic nanoparticles across blood vessel barrier for treatment of inflammation and infection. ACS Nano 9, 11800–11811 (2015).

  324. 324.

    Xue, J. et al. Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence. Nat. Nanotechnol. 12, 692–700 (2017).

  325. 325.

    Klein, C. Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes. Annu. Rev. Immunol. 29, 399–413 (2011).

  326. 326.

    Dinauer, M. C. Primary immune deficiencies with defects in neutrophil function. Hematology Am. Soc. Hematol. Educ. Program 2016, 43–50 (2016).

  327. 327.

    Nayak, R. C. et al. Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells. J. Clin. Invest. 125, 3103–3116 (2015).

  328. 328.

    Boztug, K. et al. A syndrome with congenital neutropenia and mutations in G6PC3. N. Engl. J. Med. 360, 32–43 (2009).

  329. 329.

    Boztug, K. et al. JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia. Nat. Genet. 46, 1021–1027 (2014).

  330. 330.

    Roos, D. Chronic granulomatous disease. Br. Med. Bull. 118, 50–63 (2016).

  331. 331.

    Klebanoff, S. J., Kettle, A. J., Rosen, H., Winterbourn, C. C. & Nauseef, W. M. Myeloperoxidase: a front-line defender against phagocytosed microorganisms. J. Leukoc. Biol. 93, 185–198 (2013).

  332. 332.

    Scapini, P., Marini, O., Tecchio, C. & Cassatella, M. A. Human neutrophils in the saga of cellular heterogeneity: insights and open questions. Immunol. Rev. 273, 48–60 (2016).

  333. 333.

    Silvestre-Roig, C., Hidalgo, A. & Soehnlein, O. Neutrophil heterogeneity: implications for homeostasis and pathogenesis. Blood 127, 2173–2181 (2016).

  334. 334.

    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).

  335. 335.

    Hacbarth, E. & Kajdacsy-Balla, A. Low density neutrophils in patients with systemic lupus erythematosus, rheumatoid arthritis, and acute rheumatic fever. Arthritis Rheum. 29, 1334–1342 (1986). This article reports the presence of low-density neutrophils in various autoimmune diseases.

  336. 336.

    Powell, D. R. & Huttenlocher, A. Neutrophils in the tumor microenvironment. Trends Immunol. 37, 41–52 (2016).

  337. 337.

    Tecchio, C. & Cassatella, M. A. Neutrophil-derived cytokines involved in physiological and pathological angiogenesis. Chem. Immunol. Allergy 99, 123–137 (2014).

  338. 338.

    Bronte, V. et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7, 12150 (2016).

  339. 339.

    Condamine, T. et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J. Clin. Invest. 124, 2626–2639 (2014).

  340. 340.

    Tecchio, C., Micheletti, A. & Cassatella, M. A. Neutrophil-derived cytokines: facts beyond expression. Front. Immunol. 5, 508 (2014).

  341. 341.

    Ostuni, R., Natoli, G., Cassatella, M. A. & Tamassia, N. Epigenetic regulation of neutrophil development and function. Semin. Immunol. 28, 83–93 (2016).

  342. 342.

    Kenny, E. F. et al. Diverse stimuli engage different neutrophil extracellular trap pathways. eLife 6, e24437 (2017).

  343. 343.

    Kienhofer, D. et al. Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps. JCI Insight 2, 92920 (2017).

  344. 344.

    Wang, Y. et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J. Cell Biol. 184, 205–213 (2009).

  345. 345.

    Wong, S. L. & Wagner, D. D. Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging. FASEB J 2018, fj201800691R (2018).

  346. 346.

    Guiducci, E. et al. Candida albicans-induced NETosis is independent of peptidylarginine deiminase 4. Front. Immunol. 9, 1573 (2018).

  347. 347.

    Eruslanov, E. B., Singhal, S. & Albelda, S. M. Mouse versus human neutrophils in cancer: A major knowledge gap. Trends Cancer 3, 149–160 (2017).

  348. 348.

    Ma, C. & Greten, T. F. Editorial: “invisible” MDSC in tumor-bearing individuals after antibody depletion: fact or fiction? J. Leukoc. Biol. 99, 794 (2016).

Download references

Acknowledgements

The authors apologize to the authors of numerous outstanding publications that had to be omitted due to space limitations. This work was supported by the Hungarian National Agency for Research, Development and Innovation (K-NVKP_16-1-2016-0152956, VEKOP-2.3.2-16-2016-00002 and KKP 129954 to A.M.), the European Union’s Horizon 2020 IMI2 programme (RTCure project; grant no. 777357 to A.M.) and the Deutsche Forschungsgemeinschaft (SFB 914 projects B01 and Z03, grant no. SP621/5-1 to M.S.).

Author information

Correspondence to Tamás Németh or Attila Mócsai.

Ethics declarations

Competing interests

M.S. is a scientific advisor for Dompé Farmaceutici S.p.A. The other authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Neutrophil extracellular traps

(NETs). A web of chromatin and granule proteins that are expelled from neutrophils during a unique form of cell death called ‘NETosis’ . The biological role of NETs is still debated.

Respiratory burst

The phenomenon of increased O2 consumption on neutrophil activation. It is primarily due to a non-mitochondrial mechanism through the activity of the neutrophil NADPH oxidase NOX2.

Low-density granulocytes

A subset of circulating granulocytes with unusually low density that appear in the mononuclear fraction during density gradient separation of leukocytes. Low-density granulocytes are abundant in certain autoimmune diseases, such as systemic lupus erythematosus. Their origin and functional importance in disease pathogenesis are poorly understood.

Formyl peptide receptors

G protein-coupled receptors recognizing N-formylated peptides of bacterial or mitochondrial origin during bacterial infection or tissue damage, respectively.

Swarming

The phenomenon of massive focal accumulation of neutrophils at sites of infection or tissue injury. It is likely mediated by positive-feedback amplification of neutrophil recruitment signals.

NADPH oxidase

A member of a family of transmembrane enzyme complexes leading to the generation of superoxide (O2.–) radicals. They are involved in reactive oxygen species generation by neutrophils (through NOX2), as well as several other redox signalling processes.

Peptidylarginine deiminase

A member of a family of enzymes involved in the citrullination of proteins (that is, the conversion of arginine into citrulline residues). Besides a number of biological functions, citrullination is also thought to generate neoantigens during autoimmune diseases.

CARD9

An adapter protein linking immune receptors to nuclear factor-κB activation in myeloid cells during fungal infection and other inflammatory processes.

Tyrosine kinase SYK

An intracellular tyrosine kinase mediating immunoreceptor tyrosine-based activation motif (ITAM)-based signalling by B cell receptors, Fc receptors and certain C-type lectins. SYK has diverse roles in immunity and inflammation.

Janus kinase

(JAK). A member of a family of intracellular tyrosine kinases mediating signalling by most (but not all) cytokine receptors through activation of signal transducer and activator of transcription (STAT)-family transcription factors. The JAK family consists of JAK1, JAK2, JAK3 and TYK2.

MCL1

An antiapoptotic member of the BCL-2 family present in various immune cells and overexpressed in certain tumours. MCL1 blocks the intrinsic apoptotic programme of neutrophils, and therefore MCL1 deficiency leads to severe neutropenia.

Resolution of inflammation

An active process of restoring normal tissue structure and function after an acute inflammatory insult. Defective resolution is thought to lead to chronic inflammation.

Myeloid-derived suppressor cell

(MDSC). A diverse subset of myeloid cells that promote tumour development by suppressing antitumour immunity. MDSCs may phenotypically be similar to monocytes (monocytic MDSCs) or granulocytes (granulocytic or polymorphonuclear MDSCs).

Plasmacytoid dendritic cells

A unique circulating subset of dendritic cells capable of producing large amounts of type I interferons. Besides their role in antimicrobial host defence, they likely contribute to autoimmune diseases such as systemic lupus erythematosus.

Anti-citrullinated peptide autoantibodies

(ACPAs). Autoantibodies against various citrullinated autoantigens present in a subset of patients with rheumatoid arthritis. It is still unclear how ACPAs participate in the pathogenesis of rheumatoid arthritis.

IL-23–IL-17 axis

An immune signalling pathway whereby IL-23 leads to IL-17 production by T helper 17 cells. Besides its role in antimicrobial host defence, the IL-23–IL-17 axis also participates in the development of various autoimmune and inflammatory diseases, such as psoriasis, and serves as a regulator of granulopoiesis.

Tumour-associated neutrophils

Neutrophils accumulating within the tumour tissue as one of the dominant tumour-infiltrating immune cell types in certain tumours. Tumour-associated neutrophils may exert either antitumoural (N1) or pro-tumoural (N2) effects.

Premetastatic niches

Local environments in distant secondary organs that promote the engraftment and colonization by primary tumour cells, leading to metastasis formation. Preparation of premetastatic niches begins long before the actual translocation of primary tumour cells.

Trogocytosis

A process whereby immune cells extract membrane fragments and cytoplasm from target cells by mechanically tearing out parts of the target cell. Neutrophils use trogocytosis to kill cancer cells in a process called ‘trogoptosis’.

ANCA-associated vasculitis

(AAV). Small-vessel vasculitis co-occurring with circulating antibodies against neutrophil components (anti-neutrophil cytoplasmic antibodies (ANCAs)). It is generally believed that ANCAs and ANCA-mediated neutrophil activation play a pathogenetic role in AAV.

Gout flares

The acute exacerbation of gouty arthritis, characterized by massive inflammation caused by deposition of monosodium urate crystals. Neutrophils are believed to be involved in the inflammation process during gout flares.

Endoplasmic reticulum stress

The accumulation of misfolded or unfolded proteins in the endoplasmic reticulum, for example, during prion diseases or on mutations leading to folding defects. Endoplasmic reticulum stress triggers a process called ‘unfolded protein response’ and may lead to apoptosis of the cell.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Németh, T., Sperandio, M. & Mócsai, A. Neutrophils as emerging therapeutic targets. Nat Rev Drug Discov (2020). https://doi.org/10.1038/s41573-019-0054-z

Download citation