Heterogeneity of neutrophils

Nature Reviews Immunology

Volumn 19, Issue 4, 2019, Pages 255-265

  Ng, Lai Guan ^a   Ostuni, Renato ^b,c   Hidalgo, Andrés ^d,e  

^a AGENCY FOR SCIENCE   (Singapore)

^b SAN RAFFAELE SCIENTIFIC INSTITUTE   (Italy)

^c VITA SALUTE SAN RAFFAELE UNIVERSITY   (Italy)

^d CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CNIC   (Spain)

^e LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CHEMOKINE RECEPTOR CXCR2; CHEMOKINE RECEPTOR CXCR4; GELATINASE B; GRANULOCYTE COLONY STIMULATING FACTOR;

AUTOIMMUNITY; BONE MARROW CELL; CELL DIFFERENTIATION; CELL HETEROGENEITY; CELL PROLIFERATION; DISEASE EXACERBATION; EXTRACELLULAR TRAP; GENE CONTROL; GENETIC TRANSCRIPTION; GRANULOPOIESIS; HUMAN; IMMUNE RESPONSE; NEUTROPHIL; NONHUMAN; PHAGOCYTOSIS; PHENOTYPE; POLYMERIZATION; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN EXPRESSION; REVIEW; TRANSCRIPTOMICS; ANIMAL; IMMUNOLOGY; IMMUNOPATHOLOGY; NEOPLASM;

ANIMALS; CELL DIFFERENTIATION; HUMANS; IMMUNE SYSTEM DISEASES; MYELOID CELLS; NEOPLASMS; NEUTROPHILS;

EID: 85062335210     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/s41577-019-0141-8     Document Type: Review

References (146)

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).
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).
3. Paul, F. et al. Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 163, 1663–1677 (2015).
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).
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).
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).
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).
8. 2 O reveals a human neutrophil lifespan of 5.4 days. Blood 116, 625–627 (2010).
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).
10. Dancey, J. T., Deubelbeiss, K. A., Harker, L. A. & Finch, C. A. Neutrophil kinetics in man. J. Clin. Invest. 58, 705–715 (1976).
11. Velten, L. et al. Human haematopoietic stem cell lineage commitment is a continuous process. Nat. Cell Biol. 19, 271–281 (2017).
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).
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).
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).
15. Sadik, C. D., Kim, N. D. & Luster, A. D. Neutrophils cascading their way to inflammation. Trends Immunol. 32, 452–460 (2011).
16. Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).
17. Kruger, P. et al. Neutrophils: between host defence, immune modulation, and tissue injury. PLOS Pathog. 11, e1004651 (2015).
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).
19. Phillipson, M. & Kubes, P. The neutrophil in vascular inflammation. Nat. Med. 17, 1381–1390 (2011).
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).
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).
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).
23. Wei, Q. & Frenette, P. S. Niches for hematopoietic stem cells and their progeny. Immunity 48, 632–648 (2018).
24. Bowers, E. et al. Granulocyte-derived TNFalpha promotes vascular and hematopoietic regeneration in the bone marrow. Nat. Med. 24, 95–102 (2018).
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).
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).
27. Casanova-Acebes, M. et al. Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell 153, 1025–1035 (2013).
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).
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).
30. Casanova-Acebes, M. et al. Neutrophils instruct homeostatic and pathological states in naive tissues. J. Exp. Med. 215, 2778–2795 (2018).
31. Scheiermann, C. et al. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity 37, 290–301 (2012).
32. Scheiermann, C., Frenette, P. S. & Hidalgo, A. Regulation of leucocyte homeostasis in the circulation. Cardiovasc. Res. 107, 340–351 (2015).
33. Adrover, J. M., Nicolas-Avila, J. A. & Hidalgo, A. Aging: a temporal dimension for neutrophils. Trends Immunol. 37, 334–345 (2016).
34. Adrover, J. M. et al. A neutrophil timer coordinates immune defense and vascular protection. Immunity. 10.1016/j.immuni.2019.01.002 (2019).
35. Zhang, D. et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015).
36. Man, K., Loudon, A. & Chawla, A. Immunity around the clock. Science 354, 999–1003 (2016).
37. Ella, K., Csepanyi-Komi, R. & Kaldi, K. Circadian regulation of human peripheral neutrophils. Brain Behav. Immun. 57, 209–221 (2016).
38. Scheiermann, C., Kunisaki, Y. & Frenette, P. S. Circadian control of the immune system. Nat. Rev. Immunol. 13, 190–198 (2013).
39. Scheiermann, C., Gibbs, J., Ince, L. & Loudon, A. Clocking in to immunity. Nat. Rev. Immunol. 18, 423–437 (2018).
40. Nguyen, K. D. et al. Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes. Science 341, 1483–1488 (2013).
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).
42. Steffens, S. et al. Circadian control of inflammatory processes in atherosclerosis and its complications. Arterioscler. Thromb. Vasc. Biol. 37, 1022–1028 (2017).
43. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).
44. Wynn, T. A., Chawla, A. & Pollard, J. W. Macrophage biology in development, homeostasis and disease. Nature 496, 445–455 (2013).
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).
46. Becher, B. et al. High-dimensional analysis of the murine myeloid cell system. Nat. Immunol. 15, 1181–1189 (2014).
47. Lammermann, T. et al. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498, 371–375 (2013).
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).
49. Lasarte, S. et al. Sex hormones coordinate neutrophil immunity in the vagina by controlling chemokine gradients. J. Infect. Dis. 213, 476–484 (2016).
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).
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).
52. Yipp, B. G. et al. The lung is a host defense niche for immediate neutrophil-mediated vascular protection. Sci. Immunol. 2, eaam8929 (2017).
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).
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).
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).
56. Nourshargh, S., Renshaw, S. A. & Imhof, B. A. Reverse migration of neutrophils: where, when, how, and why? Trends Immunol. 37, 273–286 (2016).
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).
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).
59. Christoffersson, G. et al. Vascular sprouts induce local attraction of proangiogenic neutrophils. J. Leukoc. Biol. 102, 741–751 (2017).
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).
61. Seignez, C. & Phillipson, M. The multitasking neutrophils and their involvement in angiogenesis. Curr. Opin. Hematol. 24, 3–8 (2017).
62. Silvestre-Roig, C., Hidalgo, A. & Soehnlein, O. Neutrophil heterogeneity: implications for homeostasis and pathogenesis. Blood 127, 2173–2181 (2016).
63. Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).
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).
65. Fridlender, Z. G. & Albelda, S. M. Tumor-associated neutrophils: friend or foe? Carcinogenesis 33, 949–955 (2012).
66. Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).
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).
68. Cortez-Retamozo, V. et al. Origins of tumor-associated macrophages and neutrophils. Proc. Natl Acad. Sci. USA 109, 2491–2496 (2012).
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).
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).
71. Mishalian, I. et al. Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression. Cancer Immunol. Immunother. 62, 1745–1756 (2013).
72. Massara, M. et al. ACKR2 in hematopoietic precursors as a checkpoint of neutrophil release and anti-metastatic activity. Nat. Commun. 9, 676 (2018).
73. Strauss, L. et al. RORC1 regulates tumor-promoting “emergency” granulo-monocytopoiesis. Cancer Cell 28, 253–269 (2015).
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).
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).
76. Manz, M. G. & Boettcher, S. Emergency granulopoiesis. Nat. Rev. Immunol. 14, 302–314 (2014).
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).
78. Sagiv, J. Y. et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 10, 562–573 (2015).
79. Engblom, C. et al. Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF(high) neutrophils. Science 358, eaal5081 (2017).
80. Massague, J. TGFbeta in cancer. Cell 134, 215–230 (2008).
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).
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).
83. Soehnlein, O., Steffens, S., Hidalgo, A. & Weber, C. Neutrophils as protagonists and targets in chronic inflammation. Nat. Rev. Immunol. 17, 248–261 (2017).
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).
85. Vandoorne, K. et al. Imaging the vascular bone marrow niche during inflammatory stress. Circ. Res. 123, 415–427 (2018).
86. Boettcher, S. et al. Endothelial cells translate pathogen signals into G-CSF-driven emergency granulopoiesis. Blood 124, 1393–1403 (2014).
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).
88. Dutta, P. et al. Myocardial infarction accelerates atherosclerosis. Nature 487, 325–329 (2012).
89. Swirski, F. K. et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612–616 (2009).
90. Fabene, P. F. et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat. Med. 14, 1377–1383 (2008).
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).
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).
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).
94. Banchereau, R. et al. Personalized immunomonitoring uncovers molecular networks that stratify lupus patients. Cell 165, 1548–1550 (2016).
95. Bennett, L. et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711–723 (2003).
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).
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).
98. Gupta, S. & Kaplan, M. J. The role of neutrophils and NETosis in autoimmune and renal diseases. Nat. Rev. Nephrol. 12, 402–413 (2016).
99. Ermert, D. et al. Mouse neutrophil extracellular traps in microbial infections. J. Innate Immun. 1, 181–193 (2009).
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).
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).
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).
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).
104. Weeding, E. et al. Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils. Clin. Immunol. 196, 110–116 (2018).
105. Zhu, Y. et al. Comprehensive characterization of neutrophil genome topology. Genes Dev. 31, 141–153 (2017).
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).
107. Chen, X. et al. ATAC-see reveals the accessible genome by transposase-mediated imaging and sequencing. Nat. Methods 13, 1013–1020 (2016).
108. Borregaard, N. Neutrophils, from marrow to microbes. Immunity 33, 657–670 (2010).
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).
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).
111. Chen, L. et al. Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell 167, 1398–1414 (2016).
112. Ecker, S. et al. Genome-wide analysis of differential transcriptional and epigenetic variability across human immune cell types. Genome Biol. 18, 18 (2017).
113. Andiappan, A. K. et al. Genome-wide analysis of the genetic regulation of gene expression in human neutrophils. Nat. Commun. 6, 7971 (2015).
114. Chatterjee, A. et al. Genome-wide DNA methylation map of human neutrophils reveals widespread inter-individual epigenetic variation. Sci. Rep. 5, 17328 (2015).
115. de Kleijn, S. et al. Transcriptome kinetics of circulating neutrophils during human experimental endotoxemia. PLOS ONE 7, e38255 (2012).
116. Naranbhai, V. et al. Genomic modulators of gene expression in human neutrophils. Nat. Commun. 6, 7545 (2015).
117. Pedersen, C. C. et al. Changes in gene expression during G-CSF-induced emergency granulopoiesis in humans. J. Immunol. 197, 1989–1999 (2016).
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).
119. Ostuni, R., Natoli, G., Cassatella, M. A. & Tamassia, N. Epigenetic regulation of neutrophil development and function. Semin. Immunol. 28, 83–93 (2016).
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).
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).
122. Glass, C. K. & Natoli, G. Molecular control of activation and priming in macrophages. Nat. Immunol. 17, 26–33 (2016).
123. Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).
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).
125. Ghisletti, S. et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity 32, 317–328 (2010).
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).
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).
128. Ostuni, R. et al. Latent enhancers activated by stimulation in differentiated cells. Cell 152, 157–171 (2013).
129. Zaret, K. S. & Mango, S. E. Pioneer transcription factors, chromatin dynamics, and cell fate control. Curr. Opin. Genet. Dev. 37, 76–81 (2016).
130. Monticelli, S. & Natoli, G. Transcriptional determination and functional specificity of myeloid cells: making sense of diversity. Nat. Rev. Immunol. 17, 595–607 (2017).
131. Veglia, F., Perego, M. & Gabrilovich, D. Myeloid-derived suppressor cells coming of age. Nat. Immunol. 19, 108–119 (2018).
132. Mullen, A. C. et al. Master transcription factors determine cell-type-specific responses to TGF-beta signaling. Cell 147, 565–576 (2011).
133. Vahedi, G. et al. STATs shape the active enhancer landscape of T cell populations. Cell 151, 981–993 (2012).
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).
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).
136. Skokowa, J., Dale, D. C., Touw, I. P., Zeidler, C. & Welte, K. Severe congenital neutropenias. Nat. Rev. Dis. Primers 3, 17032 (2017).
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).
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).
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).
140. Karsunky, H. et al. Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1. Nat. Genet. 30, 295–300 (2002).
141. Olsson, A. et al. Single-cell analysis of mixed-lineage states leading to a binary cell fate choice. Nature 537, 698–702 (2016).
142. Kurotaki, D. et al. IRF8 inhibits C/EBPalpha activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils. Nat. Commun. 5, 4978 (2014).
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).
144. Hambleton, S. et al. IRF8 mutations and human dendritic-cell immunodeficiency. N. Engl. J. Med. 365, 127–138 (2011).
145. Kurotaki, D. et al. Transcription factor IRF8 governs enhancer landscape dynamics in mononuclear phagocyte progenitors. Cell Rep. 22, 2628–2641 (2018).
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).