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  • Perspective
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OPINION

Heterogeneity of neutrophils

Abstract

Structured models of ontogenic, phenotypic and functional diversity have been instrumental for a renewed understanding of the biology of immune cells, such as macrophages and lymphoid cells. However, there are no established models that can be used to define the diversity of neutrophils, the most abundant myeloid cells. This lack of an established model is largely due to the uniquely short lives of neutrophils, a consequence of their inability to divide once terminally differentiated, which has been perceived as a roadblock to functional diversity. This perception is rapidly evolving as multiple phenotypic and functional variants of neutrophils have been found, both in homeostatic and disease conditions. In this Opinion article, we present an overview of neutrophil heterogeneity and discuss possible mechanisms of diversification, including genomic regulation. We suggest that neutrophil heterogeneity is an important feature of immune pathophysiology, such that co-option of the mechanisms of diversification by cancer or other disorders contributes to disease progression.

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Fig. 1: A framework for subset identification.
Fig. 2: The neutrophil differentiation pathway.
Fig. 3: Stages of neutrophil heterogeneity in the steady state.
Fig. 4: A model for genomic control of neutrophil heterogeneity in cancer.

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References

  1. Pillay, J., Tak, T., Kamp, V. M. & Koenderman, L. Immune suppression by neutrophils and granulocytic myeloid-derived suppressor cells: similarities and differences. Cell. Mol. Life Sci. 70, 3813–3827 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Giladi, A. et al. Single-cell characterization of haematopoietic progenitors and their trajectories in homeostasis and perturbed haematopoiesis. Nat. Cell Biol. 20, 836–846 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Fliedner, T. M., Cronkite, E. P., Killmann, S. A. & Bond, V. P. Granulocytopoiesis. II. Emergence and pattern of labeling of neutrophilic granulocytes in humans. Blood 24, 683–700 (1964).

    CAS  PubMed  Google Scholar 

  5. Lord, B. I. et al. Myeloid cell kinetics in mice treated with recombinant interleukin-3, granulocyte colony-stimulating factor (CSF), or granulocyte-macrophage CSF in vivo. Blood 77, 2154–2159 (1991).

    CAS  PubMed  Google Scholar 

  6. Basu, S., Hodgson, G., Katz, M. & Dunn, A. R. Evaluation of role of G-CSF in the production, survival, and release of neutrophils from bone marrow into circulation. Blood 100, 854–861 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Tak, T., Tesselaar, K., Pillay, J., Borghans, J. A. & Koenderman, L. What’s your age again? Determination of human neutrophil half-lives revisited. J. Leukoc. Biol. 94, 595–601 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Pillay, J. et al. In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood 116, 625–627 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Bjerregaard, M. D., Jurlander, J., Klausen, P., Borregaard, N. & Cowland, J. B. The in vivo profile of transcription factors during neutrophil differentiation in human bone marrow. Blood 101, 4322–4332 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Dancey, J. T., Deubelbeiss, K. A., Harker, L. A. & Finch, C. A. Neutrophil kinetics in man. J. Clin. Invest. 58, 705–715 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Velten, L. et al. Human haematopoietic stem cell lineage commitment is a continuous process. Nat. Cell Biol. 19, 271–281 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Kim, M. H. et al. A late-lineage murine neutrophil precursor population exhibits dynamic changes during demand-adapted granulopoiesis. Sci. Rep. 7, 39804 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Kruger, P. et al. Neutrophils: between host defence, immune modulation, and tissue injury. PLOS Pathog. 11, e1004651 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Craddock, C. G. Jr., Perry, S., Ventzke, L. E. & Lawrence, J. S. Evaluation of marrow granulocytic reserves in normal and disease states. Blood 15, 840–855 (1960).

    PubMed  Google Scholar 

  21. Donohue, D. M., Reiff, R. H., Hanson, M. L., Betson, Y. & Finch, C. A. Quantitative measurement of the erythrocytic and granulocytic cells of the marrow and blood. J. Clin. Invest. 37, 1571–1576 (1958).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Perry, S., Weinstein, I. M., Craddock, C. G. Jr & Lawrence, J. S. The combined use of typhoid vaccine and P32 labeling to assess myelopoiesis. Blood 12, 549–558 (1957).

    CAS  PubMed  Google Scholar 

  23. Wei, Q. & Frenette, P. S. Niches for hematopoietic stem cells and their progeny. Immunity 48, 632–648 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bowers, E. et al. Granulocyte-derived TNFalpha promotes vascular and hematopoietic regeneration in the bone marrow. Nat. Med. 24, 95–102 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Kawano, Y. et al. G-CSF-induced sympathetic tone provokes fever and primes antimobilizing functions of neutrophils via PGE2. Blood 129, 587–597 (2017).

    Article  CAS  PubMed  Google Scholar 

  26. Chen, X. et al. Bone marrow myeloid cells regulate myeloid-biased hematopoietic stem cells via a histamine-dependent feedback loop. Cell Stem Cell 21, 747–760 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    Article  CAS  PubMed  Google Scholar 

  29. Mendez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Scheiermann, C., Frenette, P. S. & Hidalgo, A. Regulation of leucocyte homeostasis in the circulation. Cardiovasc. Res. 107, 340–351 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. Adrover, J. M. et al. A neutrophil timer coordinates immune defense and vascular protection. Immunity. https://doi.org/10.1016/j.immuni.2019.01.002 (2019).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Man, K., Loudon, A. & Chawla, A. Immunity around the clock. Science 354, 999–1003 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ella, K., Csepanyi-Komi, R. & Kaldi, K. Circadian regulation of human peripheral neutrophils. Brain Behav. Immun. 57, 209–221 (2016).

    Article  CAS  PubMed  Google Scholar 

  38. Scheiermann, C., Kunisaki, Y. & Frenette, P. S. Circadian control of the immune system. Nat. Rev. Immunol. 13, 190–198 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Scheiermann, C., Gibbs, J., Ince, L. & Loudon, A. Clocking in to immunity. Nat. Rev. Immunol. 18, 423–437 (2018).

    Article  CAS  PubMed  Google Scholar 

  40. Nguyen, K. D. et al. Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes. Science 341, 1483–1488 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Schloss, M. J. et al. The time-of-day of myocardial infarction onset affects healing through oscillations in cardiac neutrophil recruitment. EMBO Mol. Med. 8, 937–948 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Steffens, S. et al. Circadian control of inflammatory processes in atherosclerosis and its complications. Arterioscler. Thromb. Vasc. Biol. 37, 1022–1028 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wynn, T. A., Chawla, A. & Pollard, J. W. Macrophage biology in development, homeostasis and disease. Nature 496, 445–455 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nicolas-Avila, J. A., Hidalgo, A. & Ballesteros, I. Specialized functions of resident macrophages in brain and heart. J. Leukoc. Biol. 104, 743–756 (2018).

    Article  CAS  PubMed  Google Scholar 

  46. Becher, B. et al. High-dimensional analysis of the murine myeloid cell system. Nat. Immunol. 15, 1181–1189 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Lammermann, T. et al. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498, 371–375 (2013).

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. Lasarte, S. et al. Sex hormones coordinate neutrophil immunity in the vagina by controlling chemokine gradients. J. Infect. Dis. 213, 476–484 (2016).

    Article  CAS  PubMed  Google Scholar 

  50. Wira, C. R., Rodriguez-Garcia, M. & Patel, M. V. The role of sex hormones in immune protection of the female reproductive tract. Nat. Rev. Immunol. 15, 217–230 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Devi, S. et al. Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow. J. Exp. Med. 210, 2321–2336 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yipp, B. G. et al. The lung is a host defense niche for immediate neutrophil-mediated vascular protection. Sci. Immunol. 2, eaam8929 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Deniset, J. F., Surewaard, B. G., Lee, W. Y. & Kubes, P. Splenic Ly6G(high) mature and Ly6G(int) immature neutrophils contribute to eradication of S. pneumoniae. J. Exp. Med. 214, 1333–1350 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chorny, A. et al. The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells. J. Exp. Med. 213, 2167–2185 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Puga, I. et al. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat. Immunol. 13, 170–180 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  59. Christoffersson, G. et al. Vascular sprouts induce local attraction of proangiogenic neutrophils. J. Leukoc. Biol. 102, 741–751 (2017).

    Article  CAS  PubMed  Google Scholar 

  60. Massena, S. et al. Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans. Blood 126, 2016–2026 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Seignez, C. & Phillipson, M. The multitasking neutrophils and their involvement in angiogenesis. Curr. Opin. Hematol. 24, 3–8 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  63. Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bonavita, E., Galdiero, M. R., Jaillon, S. & Mantovani, A. Phagocytes as corrupted policemen in cancer-related inflammation. Adv. Cancer Res. 128, 141–171 (2015).

    Article  PubMed  Google Scholar 

  65. Fridlender, Z. G. & Albelda, S. M. Tumor-associated neutrophils: friend or foe? Carcinogenesis 33, 949–955 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Guthrie, G. J. et al. The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Crit. Rev. Oncol. Hematol. 88, 218–230 (2013).

    Article  PubMed  Google Scholar 

  68. Cortez-Retamozo, V. et al. Origins of tumor-associated macrophages and neutrophils. Proc. Natl Acad. Sci. USA 109, 2491–2496 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Galdiero, M. R., Varricchi, G., Loffredo, S., Mantovani, A. & Marone, G. Roles of neutrophils in cancer growth and progression. J. Leukoc. Biol. 103, 457–464 (2018).

    Article  CAS  PubMed  Google Scholar 

  71. Mishalian, I. et al. Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression. Cancer Immunol. Immunother. 62, 1745–1756 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Massara, M. et al. ACKR2 in hematopoietic precursors as a checkpoint of neutrophil release and anti-metastatic activity. Nat. Commun. 9, 676 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Strauss, L. et al. RORC1 regulates tumor-promoting “emergency” granulo-monocytopoiesis. Cancer Cell 28, 253–269 (2015).

    Article  CAS  PubMed  Google Scholar 

  74. Quail, D. F. et al. Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF. Nat. Cell Biol. 19, 974–987 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Youn, J. I., Collazo, M., Shalova, I. N., Biswas, S. K. & Gabrilovich, D. I. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J. Leukoc. Biol. 91, 167–181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Massague, J. TGFbeta in cancer. Cell 134, 215–230 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Andzinski, L. et al. Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human. Int. J. Cancer 138, 1982–1993 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Soehnlein, O., Steffens, S., Hidalgo, A. & Weber, C. Neutrophils as protagonists and targets in chronic inflammation. Nat. Rev. Immunol. 17, 248–261 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Vandoorne, K. et al. Imaging the vascular bone marrow niche during inflammatory stress. Circ. Res. 123, 415–427 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Boettcher, S. et al. Endothelial cells translate pathogen signals into G-CSF-driven emergency granulopoiesis. Blood 124, 1393–1403 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Marini, O. et al. Mature CD10(+) and immature CD10(-) neutrophils present in G-CSF-treated donors display opposite effects on T cells. Blood 129, 1343–1356 (2017).

    Article  CAS  PubMed  Google Scholar 

  88. Dutta, P. et al. Myocardial infarction accelerates atherosclerosis. Nature 487, 325–329 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Swirski, F. K. et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612–616 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Fabene, P. F. et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat. Med. 14, 1377–1383 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  92. Cuartero, M. I., Ballesteros, I., Lizasoain, I. & Moro, M. A. Complexity of the cell-cell interactions in the innate immune response after cerebral ischemia. Brain Res. 1623, 53–62 (2015).

    Article  CAS  PubMed  Google Scholar 

  93. Cuartero, M. I. et al. N2 neutrophils, novel players in brain inflammation after stroke: modulation by the PPARgamma agonist rosiglitazone. Stroke 44, 3498–3508 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Banchereau, R. et al. Personalized immunomonitoring uncovers molecular networks that stratify lupus patients. Cell 165, 1548–1550 (2016).

    Article  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Lood, C. et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, 146–153 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ermert, D. et al. Mouse neutrophil extracellular traps in microbial infections. J. Innate Immun. 1, 181–193 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Denny, M. F. et al. A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs. J. Immunol. 184, 3284–3297 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Villanueva, E. et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J. Immunol. 187, 538–552 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Carlucci, P. M. et al. Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus. JCI Insight 3, 99276 (2018).

    Article  PubMed  Google Scholar 

  103. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Weeding, E. et al. Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils. Clin. Immunol. 196, 110–116 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Zhu, Y. et al. Comprehensive characterization of neutrophil genome topology. Genes Dev. 31, 141–153 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Carvalho, L. O., Aquino, E. N., Neves, A. C. & Fontes, W. The neutrophil nucleus and its role in neutrophilic function. J. Cell. Biochem. 116, 1831–1836 (2015).

    Article  CAS  PubMed  Google Scholar 

  107. Chen, X. et al. ATAC-see reveals the accessible genome by transposase-mediated imaging and sequencing. Nat. Methods 13, 1013–1020 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  109. Grassi, L. et al. Dynamics of transcription regulation in human bone marrow myeloid differentiation to mature blood neutrophils. Cell Rep. 24, 2784–2794 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ronnerblad, M. et al. Analysis of the DNA methylome and transcriptome in granulopoiesis reveals timed changes and dynamic enhancer methylation. Blood 123, e79–e89 (2014).

    Article  PubMed  CAS  Google Scholar 

  111. Chen, L. et al. Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell 167, 1398–1414 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ecker, S. et al. Genome-wide analysis of differential transcriptional and epigenetic variability across human immune cell types. Genome Biol. 18, 18 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Andiappan, A. K. et al. Genome-wide analysis of the genetic regulation of gene expression in human neutrophils. Nat. Commun. 6, 7971 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Chatterjee, A. et al. Genome-wide DNA methylation map of human neutrophils reveals widespread inter-individual epigenetic variation. Sci. Rep. 5, 17328 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. de Kleijn, S. et al. Transcriptome kinetics of circulating neutrophils during human experimental endotoxemia. PLOS ONE 7, e38255 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Naranbhai, V. et al. Genomic modulators of gene expression in human neutrophils. Nat. Commun. 6, 7545 (2015).

    Article  PubMed  Google Scholar 

  117. Pedersen, C. C. et al. Changes in gene expression during G-CSF-induced emergency granulopoiesis in humans. J. Immunol. 197, 1989–1999 (2016).

    Article  CAS  PubMed  Google Scholar 

  118. Thomas, H. B., Moots, R. J., Edwards, S. W. & Wright, H. L. Whose gene is it anyway? The effect of preparation purity on neutrophil transcriptome studies. PLOS ONE 10, e0138982 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  120. Zimmermann, M. et al. Chromatin remodelling and autocrine TNFalpha are required for optimal interleukin-6 expression in activated human neutrophils. Nat. Commun. 6, 6061 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Tamassia, N. et al. Cutting edge: an inactive chromatin configuration at the IL-10 locus in human neutrophils. J. Immunol. 190, 1921–1925 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. Glass, C. K. & Natoli, G. Molecular control of activation and priming in macrophages. Nat. Immunol. 17, 26–33 (2016).

    Article  CAS  PubMed  Google Scholar 

  123. Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Lavin, Y., Mortha, A., Rahman, A. & Merad, M. Regulation of macrophage development and function in peripheral tissues. Nat. Rev. Immunol. 15, 731–744 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ghisletti, S. et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity 32, 317–328 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Garber, M. et al. A high-throughput chromatin immunoprecipitation approach reveals principles of dynamic gene regulation in mammals. Mol. Cell 47, 810–822 (2012).

    Article  CAS  PubMed  Google Scholar 

  128. Ostuni, R. et al. Latent enhancers activated by stimulation in differentiated cells. Cell 152, 157–171 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Zaret, K. S. & Mango, S. E. Pioneer transcription factors, chromatin dynamics, and cell fate control. Curr. Opin. Genet. Dev. 37, 76–81 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Monticelli, S. & Natoli, G. Transcriptional determination and functional specificity of myeloid cells: making sense of diversity. Nat. Rev. Immunol. 17, 595–607 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Mullen, A. C. et al. Master transcription factors determine cell-type-specific responses to TGF-beta signaling. Cell 147, 565–576 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Vahedi, G. et al. STATs shape the active enhancer landscape of T cell populations. Cell 151, 981–993 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Kohler, A. et al. G-CSF-mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands. Blood 117, 4349–4357 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Skokowa, J., Dale, D. C., Touw, I. P., Zeidler, C. & Welte, K. Severe congenital neutropenias. Nat. Rev. Dis. Primers 3, 17032 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Yamanaka, R. et al. Impaired granulopoiesis, myelodysplasia, and early lethality in CCAAT/enhancer binding protein epsilon-deficient mice. Proc. Natl Acad. Sci. USA 94, 13187–13192 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Shahrin, N. H., Diakiw, S., Dent, L. A., Brown, A. L. & D’Andrea, R. J. Conditional knockout mice demonstrate function of Klf5 as a myeloid transcription factor. Blood 128, 55–59 (2016).

    Article  CAS  PubMed  Google Scholar 

  139. Skokowa, J. et al. LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nat. Med. 12, 1191–1197 (2006).

    Article  CAS  PubMed  Google Scholar 

  140. Karsunky, H. et al. Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1. Nat. Genet. 30, 295–300 (2002).

    Article  PubMed  Google Scholar 

  141. Olsson, A. et al. Single-cell analysis of mixed-lineage states leading to a binary cell fate choice. Nature 537, 698–702 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Kurotaki, D. et al. IRF8 inhibits C/EBPalpha activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils. Nat. Commun. 5, 4978 (2014).

    Article  CAS  PubMed  Google Scholar 

  143. Yanez, A., Ng, M. Y., Hassanzadeh-Kiabi, N. & Goodridge, H. S. IRF8 acts in lineage-committed rather than oligopotent progenitors to control neutrophil versus monocyte production. Blood 125, 1452–1459 (2015).

    Article  CAS  PubMed  Google Scholar 

  144. Hambleton, S. et al. IRF8 mutations and human dendritic-cell immunodeficiency. N. Engl. J. Med. 365, 127–138 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kurotaki, D. et al. Transcription factor IRF8 governs enhancer landscape dynamics in mononuclear phagocyte progenitors. Cell Rep. 22, 2628–2641 (2018).

    Article  CAS  PubMed  Google Scholar 

  146. Mancino, A. et al. A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages. Genes Dev. 29, 394–408 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are grateful to members of their laboratories for continued enthusiasm and discussions, which are reflected in many parts of this text, and to J. M. Adrover and I. Kwok for the original artwork. The authors apologize to the many colleagues whose contributions could not be discussed in this manuscript. This article is supported by Singapore Immunology Network (A*STAR) core funding to L.G.N. This paper is also supported in part by SAF2015-65607-R and Fondo Europeo de Desarrollo Regional (FEDER) to A.H. The Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) is supported by the Ministerio de Ciencia, Innovacion y Universidades (MCIU) and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (MCIU award SEV-2015-0505). Research in the R.O. laboratory is supported by grants from the European Research Council (ERC Starting Grant # 759532, X-TAM), the Italian Telethon Foundation (SR-Tiget grant award F04), the Italian Ministry of Health (GR-2016-02362156), the Associazione Italiana per la Ricerca sul Cancro (AIRC MFAG, #20247), the Cariplo Foundation (2015–0990) and the European Union (Infect-ERA #126).

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Ng, L.G., Ostuni, R. & Hidalgo, A. Heterogeneity of neutrophils. Nat Rev Immunol 19, 255–265 (2019). https://doi.org/10.1038/s41577-019-0141-8

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