Neutrophil development at single cell resolution

Neutrophils are involved in bactericidal  functions  and play  essential 
roles in host defense response. It has been identified that many genes (e.g. 
GFI1,  ELANE,  HAX1, and CSF3R)  are  critical  for  the  development  of 
neutrophils.  Individuals  who  carry  any  dysfunctional  mutations  of  these 
genes  cause  severe  congenital  neutropenia,  which is  characterized  as 
impaired  maturation  of  neutrophils. A supply  shortage  of neutrophils can
lead  to  serious  consequence,  and  it  may  cause  death  due  to severe 
infection. What’s  more, elderly people are more  susceptible  to pathogen 
invading  that  is  partially  resulted  from  dysfunctional  development  of 
neutrophils. However, current  studies  uncovered  limited  information for
potential molecular regulations, it hence is absolute necessary to elucidate
further underlying  mechanisms  of  neutrophil  development in  young  and 
aging. 
In this study, recently developed state-of-art single cell technique was 
employed for profiling transcriptome of cells in bone marrow and peripheral 
blood. To comprehensively identify developmental trajectory of neutrophils, 
a novel quality control strategy was proposed in consideration of natural 
attributes of low RNA content for mature neutrophils. Applying this strategy 
for  a  published  dataset  of  single  RNA  sequencing  (scRNA-seq) resulted 
more than 21, 000 newly identified cells, which confirmed its tremendous
power  for  recognizing  low  RNA  content  cells. Adopting  this  strategy, we 
profiled single cell transcriptome from 106, 077 cells in bone marrow and
peripheral blood of young and aging mice. 
Initially, developmental trajectory of neutrophils in bone marrow under 
homeostasis of young mice was characterized in detail. Our results revealed
a  series of  extraordinary  heterogeneous neutrophil  subsets  of  four 
previously reported stages (proNeu, preNeu, immNeu, and matNeu), which
indicated  their  complex dynamic  developmental progress.  And  these 
neutrophil  subsets  in  peripheral  blood  compartment exhibited enormous 
phenotypic  differences. Along their  differentiation  lineage,  we  identified 
some increasingly expressed potential driver genes (e.g. Gfi1, Cebpe, Jdp2, 
and  Tfec) with  probable  important  roles  during  fate  determination. And 
expression  landscape  of neutrophil  development  was found  gradually 
altered, which represented their strictly regulated  maturation  processes.
Furthermore,  our  cellular  communication  analysis  investigated  their 
complex characters in cell-cell interactions of secreted signaling, cell-cell 
contact, and ECM-receptor. Of our great interests are IL1, CCL, and CXCL 
signaling  pathways,  which  showed  distinct  outgoing  and  incoming 
communication patterns for these neutrophil subsets. Notably, our results
interpreted  developmental  dependent molecular  basis  of their signaling
transduction. 
Our comparative exploration of single cell transcriptome in aging mice 
confirmed dramatical alterations of neutrophil development, including their 
trajectory  and  transcriptional  phenotypes.  We  found aging  introduced 
oxidative  stress  to neutrophils  and reduced  their  ability  in  bacterial 
recognition, migration, and activation. Besides, aging related alterations of
signaling pathways, including IL1, CCL, and CXCL, were identified from our 
comparative cellular  communication  analysis.  Interestingly,  our  results 
revealed aging  related decreased  signaling  effects  of IL1  and  CCL  for 
neutrophil subsets in consist of their decreasingly expressed receptors but 
despite of their increasingly expressed ligands.
In  summary,  this  study uncovered  neutrophil  heterogeneity in  bone 
marrow and peripheral blood of mice, and identified aging related alterations 
that reflected molecular bases of their dysfunctional states. 

Abdel-Azim, H., W. Sun and L. Wu (2019). "Strategies to generate functionally normal neutrophils to reduce infection and infection-related mortality in cancer chemotherapy." Pharmacol Ther 204: 107403.Aken, B. L., S. Ayling, D. Barrell, L. Clarke, V. Curwen, S. Fairley, J. Fernandez Banet, K. Billis, C. Garcia Giron, T. Hourlier, K. Howe, A. Kahari, F. Kokocinski, F. J. Martin, D. N. Murphy, R. Nag, M. Ruffier, M. Schuster, Y. A. Tang, J. H. Vogel, S. White, A. Zadissa, P. Flicek and S. M. Searle (2016). "The Ensembl gene annotation system." Database (Oxford) 2016.Al Ustwani, O., R. Kurzrock and M. Wetzler (2014). "Genetics on a WHIM." Br J Haematol 164(1): 15-23.Ambros, V. (2004). "The functions of animal microRNAs." Nature 431(7006): 350-355.Andrade, D., M. Velinder, J. Singer, L. Maese, D. Bareyan, H. Nguyen, M. B. Chandrasekharan, H. Lucente, D. McClellan, D. Jones, S. Sharma, F. Liu and M. E. Engel (2016). "SUMOylation Regulates Growth Factor Independence 1 in Transcriptional Control and Hematopoiesis." Mol Cell Biol 36(10): 1438-1450.Antonson, P., B. Stellan, R. Yamanaka and K. G. Xanthopoulos (1996). "A novel human CCAAT/enhancer binding protein gene, C/EBPepsilon, is expressed in cells of lymphoid and myeloid lineages and is localized on chromosome 14q11.2 close to the T-cell receptor alpha/delta locus." Genomics 35(1): 30-38.Athanasiadis, E. I., J. G. Botthof, H. Andres, L. Ferreira, P. Lio and A. Cvejic (2017). "Single-cell RNA-sequencing uncovers transcriptional states and fate decisions in haematopoiesis." Nature Communications 8: 11.Baglama, J. and L. Reichel (2005). "Augmented implicitly restarted Lanczos bidiagonalization methods." Siam Journal on Scientific Computing 27(1): 19-42.Bailey, K. L., L. M. Smith, A. J. Heires, D. M. Katafiasz, D. J. Romberger and T. D. LeVan (2019). "Aging leads to dysfunctional innate immune responses to TLR2 and TLR4 agonists." Aging Clin Exp Res 31(9): 1185-1193.Bainton, D. F., J. L. Ullyot and M. G. Farquhar (1971). "The development of neutrophilic polymorphonuclear leukocytes in human bone marrow." J Exp Med 134(4): 907-934.Ballesteros, I., A. Rubio-Ponce, M. Genua, E. Lusito, I. Kwok, G. Fernández-Calvo, T. E. Khoyratty, E. van Grinsven, S. González-Hernández, J. Á. Nicolás-Ávila, T. Vicanolo, A. Maccataio, A. Benguría, J. L. Li, J. M. Adrover, A. Aroca-Crevillen, J. A. Quintana, S. Martín-Salamanca, F. Mayo, S. Ascher, G. Barbiera, O. Soehnlein, M. Gunzer, F. Ginhoux, F. Sánchez-Cabo, E. Nistal-Villán, C. Schulz, A. Dopazo, C. Reinhardt, I. A. Udalova, L. G. Ng, R. Ostuni and A. Hidalgo (2020). "Co-option of Neutrophil Fates by Tissue Environments." Cell.Bararia, D., H. S. Kwok, R. S. Welner, A. Numata, M. B. Sarosi, H. Yang, S. Wee, S. Tschuri, D. Ray, O. Weigert, E. Levantini, A. K. Ebralidze, J. Gunaratne and D. G. Tenen (2016). "Acetylation of C/EBPalpha inhibits its granulopoietic function." Nat Commun 7: 10968.Bargatze, R. F., S. Kurk, E. C. Butcher and M. A. Jutila (1994). "Neutrophils roll on adherent neutrophils bound to cytokine-induced endothelial cells via L-selectin on the rolling cells." J Exp Med 180(5): 1785-1792.Barkaway, A., L. Rolas, R. Joulia, J. Bodkin, T. Lenn, C. Owen-Woods, N. Reglero-Real, M. Stein, L. Vazquez-Martinez, T. Girbl, R. N. Poston, M. Golding, R. S. Saleeb, A. Thiriot, U. H. von Andrian, J. Duchene, M. B. Voisin, C. L. Bishop, D. Voehringer, A. Roers, A. Rot, T. Lammermann and S. Nourshargh (2021). "Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage." Immunity 54(7): 1494-1510 e1497.Bartel, D. P. (2004). "MicroRNAs: genomics, biogenesis, mechanism, and function." Cell 116(2): 281-297.Basu, S., G. Hodgson, M. Katz and A. R. Dunn (2002). "Evaluation of role of G-CSF in the production, survival, and release of neutrophils from bone marrow into circulation." Blood 100(3): 854-861.Becht, E., L. McInnes, J. Healy, C. A. Dutertre, I. W. H. Kwok, L. G. Ng, F. Ginhoux and E. W. Newell (2018). "Dimensionality reduction for visualizing single-cell data using UMAP." Nat Biotechnol.Becht, E., D. Tolstrup, C.-A. Dutertre, F. Ginhoux, E. W. Newell, R. Gottardo and M. B. Headley (2020). "Infinity Flow: High-throughput single-cell quantification of 100s of proteins using conventional flow cytometry and machine learning." bioRxiv.Bedi, R., J. Du, A. K. Sharma, I. Gomes and S. J. Ackerman (2009). "Human C/EBP-epsilon activator and repressor isoforms differentially reprogram myeloid lineage commitment and differentiation." Blood 113(2): 317-327.Beerman, I., D. Bhattacharya, S. Zandi, M. Sigvardsson, I. L. Weissman, D. Bryder and D. J. Rossi (2010). "Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion." Proc Natl Acad Sci U S A 107(12): 5465-5470.Begley, C. G., D. Metcalf and N. A. Nicola (1987). "Primary human myeloid leukemia cells: comparative responsiveness to proliferative stimulation by GM-CSF or G-CSF and membrane expression of CSF receptors." Leukemia 1(1): 1-8.Benayoun, B. A., E. A. Pollina, P. P. Singh, S. Mahmoudi, I. Harel, K. M. Casey, B. W. Dulken, A. Kundaje and A. Brunet (2019). "Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses." Genome Res 29(4): 697-709.Birkenmeier, E. H., B. Gwynn, S. Howard, J. Jerry, J. I. Gordon, W. H. Landschulz and S. L. McKnight (1989). "Tissue-specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein." Genes Dev 3(8): 1146-1156.Bjerregaard, M. D., J. Jurlander, P. Klausen, N. Borregaard and J. B. Cowland (2003). "The in vivo profile of transcription factors during neutrophil differentiation in human bone marrow." Blood 101(11): 4322-4332.Boeltz, S., P. Amini, H. J. Anders, F. Andrade, R. Bilyy, S. Chatfield, I. Cichon, D. M. Clancy, J. Desai, T. Dumych, N. Dwivedi, R. A. Gordon, J. Hahn, A. Hidalgo, M. H. Hoffmann, M. J. Kaplan, J. S. Knight, E. Kolaczkowska, P. Kubes, M. Leppkes, A. A. Manfredi, S. J. Martin, C. Maueroder, N. Maugeri, I. Mitroulis, L. E. Munoz, D. Nakazawa, I. Neeli, V. Nizet, E. Pieterse, M. Z. Radic, C. Reinwald, K. Ritis, P. Rovere-Querini, M. Santocki, C. Schauer, G. Schett, M. J. Shlomchik, H. U. Simon, P. Skendros, D. Stojkov, P. Vandenabeele, T. V. Berghe, J. van der Vlag, L. Vitkov, M. von Kockritz-Blickwede, S. Yousefi, A. Zarbock and M. Herrmann (2019). "To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps." Cell Death Differ 26(3): 395-408.Boivin, G., J. Faget, P. B. Ancey, A. Gkasti, J. Mussard, C. Engblom, C. Pfirschke, C. Contat, J. Pascual, J. Vazquez, N. Bendriss-Vermare, C. Caux, M. C. Vozenin, M. J. Pittet, M. Gunzer and E. Meylan (2020). "Durable and controlled depletion of neutrophils in mice." Nat Commun 11(1): 2762.Born, J., D. Uthgenannt, C. Dodt, D. Nunninghoff, E. Ringvolt, T. Wagner and H. L. Fehm (1995). "Cytokine production and lymphocyte subpopulations in aged humans. An assessment during nocturnal sleep." Mech Ageing Dev 84(2): 113-126.Borregaard, N. (2010). "Neutrophils, from marrow to microbes." Immunity 33(5): 657-670.Branzk, N., A. Lubojemska, S. E. Hardison, Q. Wang, M. G. Gutierrez, G. D. Brown and V. Papayannopoulos (2014). "Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens." Nat Immunol 15(11): 1017-1025.Brender, E., C. Lynm and R. M. Glass (2006). "JAMA patient page. Granulocyte-colony stimulating factor." JAMA 295(9): 1088.Brinkmann, V., U. Reichard, C. Goosmann, B. Fauler, Y. Uhlemann, D. S. Weiss, Y. Weinrauch and A. Zychlinsky (2004). "Neutrophil extracellular traps kill bacteria." Science 303(5663): 1532-1535.Burdon, P. C., C. Martin and S. M. Rankin (2005). "The CXC chemokine MIP-2 stimulates neutrophil mobilization from the rat bone marrow in a CD49d-dependent manner." Blood 105(6): 2543-2548.Burdon, P. C., C. Martin and S. M. Rankin (2008). "Migration across the sinusoidal endothelium regulates neutrophil mobilization in response to ELR + CXC chemokines." Br J Haematol 142(1): 100-108.Burn, G. L., A. Foti, G. Marsman, D. F. Patel and A. Zychlinsky (2021). "The Neutrophil." Immunity 54(7): 1377-1391.Butler, A., P. Hoffman, P. Smibert, E. Papalexi and R. Satija (2018). "Integrating single-cell transcriptomic data across different conditions, technologies, and species." Nat Biotechnol 36(5): 411-420.Cacalano, G., J. Lee, K. Kikly, A. M. Ryan, S. Pitts-Meek, B. Hultgren, W. I. Wood and M. W. Moore (1994). "Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog." Science 265(5172): 682-684.Cartwright, G. E., J. W. Athens and M. M. Wintrobe (1964). "The Kinetics of Granulopoiesis in Normal Man." Blood 24: 780-803.Castelo-Branco, C. and I. Soveral (2014). "The immune system and aging: a review." Gynecological Endocrinology 30(1): 16-22.Chatta, G. S., R. G. Andrews, E. Rodger, M. Schrag, W. P. Hammond and D. C. Dale (1993). "Hematopoietic progenitors and aging: alterations in granulocytic precursors and responsiveness to recombinant human G-CSF, GM-CSF, and IL-3." J Gerontol 48(5): M207-212.Chatta, G. S., T. H. Price, R. C. Allen and D. C. Dale (1994). "Effects of in vivo recombinant methionyl human granulocyte colony-stimulating factor on the neutrophil response and peripheral blood colony-forming cells in healthy young and elderly adult volunteers." Blood 84(9): 2923-2929.Chen, C. Z., L. Li, H. F. Lodish and D. P. Bartel (2004). "MicroRNAs modulate hematopoietic lineage differentiation." Science 303(5654): 83-86.Chen, H. D., F. Ye and G. J. Guo (2019). "Revolutionizing immunology with single-cell RNA sequencing." Cellular & Molecular Immunology 16(3): 242-249.Chinn, I. K., C. C. Blackburn, N. R. Manley and G. D. Sempowski (2012). "Changes in primary lymphoid organs with aging." Semin Immunol 24(5): 309-320.Cho, H., O. Kamenyeva, S. Yung, J. L. Gao, I. Y. Hwang, C. Park, P. M. Murphy, R. R. Neubig and J. H. Kehrl (2012). "The loss of RGS protein-Galpha(i2) interactions results in markedly impaired mouse neutrophil trafficking to inflammatory sites." Mol Cell Biol 32(22): 4561-4571.Choudhury, S. R., L. Babes, J. J. Rahn, B. Y. Ahn, K. R. Goring, J. C. King, A. Lau, B. Petri, X. Hao, A. K. Chojnacki, A. Thanabalasuriar, E. F. McAvoy, S. Tabaries, C. Schraeder, K. D. Patel, P. M. Siegel, K. A. Kopciuk, D. C. Schriemer, D. A. Muruve, M. M. Kelly, B. G. Yipp, P. Kubes, S. M. Robbins and D. L. Senger (2019). "Dipeptidase-1 Is an Adhesion Receptor for Neutrophil Recruitment in Lungs and Liver." Cell 178(5): 1205-1221 e1217.Chung, Y., S. H. Chang, G. J. Martinez, X. O. Yang, R. Nurieva, H. S. Kang, L. Ma, S. S. Watowich, A. M. Jetten, Q. Tian and C. Dong (2009). "Critical regulation of early Th17 cell differentiation by interleukin-1 signaling." Immunity 30(4): 576-587.Cohen, A. M., K. M. Zsebo, H. Inoue, D. Hines, T. C. Boone, V. R. Chazin, L. Tsai, T. Ritch and L. M. Souza (1987). "In vivo stimulation of granulopoiesis by recombinant human granulocyte colony-stimulating factor." Proc Natl Acad Sci U S A 84(8): 2484-2488.Collerton, J., C. Martin-Ruiz, K. Davies, C. M. Hilkens, J. Isaacs, C. Kolenda, C. Parker, M. Dunn, M. Catt, C. Jagger, T. von Zglinicki and T. B. Kirkwood (2012). "Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: cross-sectional findings from the Newcastle 85+ Study." Mech Ageing Dev 133(6): 456-466.Colotta, F., F. Re, N. Polentarutti, S. Sozzani and A. Mantovani (1992). "Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products." Blood 80(8): 2012-2020.Condliffe, A. M., E. Kitchen and E. R. Chilvers (1998). "Neutrophil priming: pathophysiological consequences and underlying mechanisms." Clin Sci (Lond) 94(5): 461-471.Corey, S. J. and S. M. Anderson (1999). "Src-related protein tyrosine kinases in hematopoiesis." Blood 93(1): 1-14.Cowland, J. B. and N. Borregaard (2016). "Granulopoiesis and granules of human neutrophils." Immunol Rev 273(1): 11-28.Dahlin, J. S., F. K. Hamey, B. Pijuan-Sala, M. Shepherd, W. W. Y. Lau, S. Nestorowa, C. Weinreb, S. Wolock, R. Hannah, E. Diamanti, D. G. Kent, B. Gottgens and N. K. Wilson (2018). "A single-cell hematopoietic landscape resolves 8 lineage trajectories and defects in Kit mutant mice." Blood 131(21): e1-e11.Dancey, J. T., K. A. Deubelbeiss, L. A. Harker and C. A. Finch (1976). "Neutrophil kinetics in man." J Clin Invest 58(3): 705-715.Day, R. B. and D. C. Link (2012). "Regulation of neutrophil trafficking from the bone marrow." Cell Mol Life Sci 69(9): 1415-1423.de la Luz Sierra, M., S. Sakakibara, P. Gasperini, O. Salvucci, K. Jiang, P. J. McCormick, M. Segarra, J. Stone, D. Maric, J. Zhu, X. Qian, D. R. Lowy and G. Tosato (2010). "The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1." Blood 115(19): 3970-3979.De Martinis, M., M. Modesti and L. Ginaldi (2004). "Phenotypic and functional changes of circulating monocytes and polymorphonuclear leucocytes from elderly persons." Immunol Cell Biol 82(4): 415-420.Demetri, G. D. and J. D. Griffin (1991). "Granulocyte colony-stimulating factor and its receptor." Blood 78(11): 2791-2808.Descombes, P. and U. Schibler (1991). "A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA." Cell 67(3): 569-579.Diaz, G. A. (2005). "CXCR4 mutations in WHIM syndrome: a misguided immune system?" Immunol Rev 203: 235-243.Dobin, A., C. A. Davis, F. Schlesinger, J. Drenkow, C. Zaleski, S. Jha, P. Batut, M. Chaisson and T. R. Gingeras (2013). "STAR: ultrafast universal RNA-seq aligner." Bioinformatics 29(1): 15-21.Dong, F., R. K. Brynes, N. Tidow, K. Welte, B. Lowenberg and I. P. Touw (1995). "Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia." N Engl J Med 333(8): 487-493.Dong, F., D. C. Dale, M. A. Bonilla, M. Freedman, A. Fasth, H. J. Neijens, J. Palmblad, G. L. Briars, G. Carlsson, A. J. Veerman, K. Welte, B. Lowenberg and I. P. Touw (1997). "Mutations in the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia." Leukemia 11(1): 120-125.Dong, F., L. H. Hoefsloot, A. M. Schelen, C. A. Broeders, Y. Meijer, A. J. Veerman, I. P. Touw and B. Lowenberg (1994). "Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia." Proc Natl Acad Sci U S A 91(10): 4480-4484.Doring, Y., P. Libby and O. Soehnlein (2020). "Neutrophil Extracellular Traps Participate in Cardiovascular Diseases: Recent Experimental and Clinical Insights." Circ Res 126(9): 1228-1241.Drifte, G., I. Dunn-Siegrist, P. Tissieres and J. Pugin (2013). "Innate immune functions of immature neutrophils in patients with sepsis and severe systemic inflammatory response syndrome." Crit Care Med 41(3): 820-832.Duan, Z. and M. Horwitz (2003). "Targets of the transcriptional repressor oncoprotein Gfi-1." Proc Natl Acad Sci U S A 100(10): 5932-5937.Dura, B., J. Y. Choi, K. Zhang, W. Damsky, D. Thakral, M. Bosenberg, J. Craft and R. Fan (2019). "scFTD-seq: freeze-thaw lysis based, portable approach toward highly distributed single-cell 3' mRNA profiling." Nucleic Acids Res 47(3): e16.Dutertre, C. A., E. Becht, S. E. Irac, A. Khalilnezhad, V. Narang, S. Khalilnezhad, P. Y. Ng, L. L. van den Hoogen, J. Y. Leong, B. Lee, M. Chevrier, X. M. Zhang, P. J. A. Yong, G. Koh, J. Lum, S. W. Howland, E. Mok, J. Chen, A. Larbi, H. K. K. Tan, T. K. H. Lim, P. Karagianni, A. G. Tzioufas, B. Malleret, J. Brody, S. Albani, J. van Roon, T. Radstake, E. W. Newell and F. Ginhoux (2019). "Single-Cell Analysis of Human Mononuclear Phagocytes Reveals Subset-Defining Markers and Identifies Circulating Inflammatory Dendritic Cells." Immunity 51(3): 573-589 e578.Dwivedi, P. and K. D. Greis (2017). "Granulocyte colony-stimulating factor receptor signaling in severe congenital neutropenia, chronic neutrophilic leukemia, and related malignancies." Exp Hematol 46: 9-20.Dykstra, B., S. Olthof, J. Schreuder, M. Ritsema and G. de Haan (2011). "Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells." J Exp Med 208(13): 2691-2703.Eash, K. J., A. M. Greenbaum, P. K. Gopalan and D. C. Link (2010). "CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow." J Clin Invest 120(7): 2423-2431.Eash, K. J., J. M. Means, D. W. White and D. C. Link (2009). "CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions." Blood 113(19): 4711-4719.Edgeworth, J., M. Gorman, R. Bennett, P. Freemont and N. Hogg (1991). "Identification of p8,14 as a highly abundant heterodimeric calcium binding protein complex of myeloid cells." J Biol Chem 266(12): 7706-7713.Evrard, M., I. W. H. Kwok, S. Z. Chong, K. W. W. Teng, E. Becht, J. Chen, J. L. Sieow, H. L. Penny, G. C. Ching, S. Devi, J. M. Adrover, J. L. Y. Li, K. H. Liong, L. Tan, Z. Poon, S. Foo, J. W. Chua, I. H. Su, K. Balabanian, F. Bachelerie, S. K. Biswas, A. Larbi, W. Y. K. Hwang, V. Madan, H. P. Koeffler, S. C. Wong, E. W. Newell, A. Hidalgo, F. Ginhoux and L. G. Ng (2018). "Developmental Analysis of Bone Marrow Neutrophils Reveals Populations Specialized in Expansion, Trafficking, and Effector Functions." Immunity 48(2): 364-+.Fan, H. B., Y. J. Liu, L. Wang, T. T. Du, M. Dong, L. Gao, Z. Z. Meng, Y. Jin, Y. Chen, M. Deng, H. T. Yang, Q. Jing, A. H. Gu, T. X. Liu and Y. Zhou (2014). "miR-142-3p acts as an essential modulator of neutrophil development in zebrafish." Blood 124(8): 1320-1330.Fazi, F., A. Rosa, A. Fatica, V. Gelmetti, M. L. De Marchis, C. Nervi and I. Bozzoni (2005). "A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis." Cell 123(5): 819-831.Fiedler, K. and C. Brunner (2012). "The role of transcription factors in the guidance of granulopoiesis." Am J Blood Res 2(1): 57-65.Ford, A. M., C. A. Bennett, L. E. Healy, M. Towatari, M. F. Greaves and T. Enver (1996). "Regulation of the myeloperoxidase enhancer binding proteins Pu1, C-EBP alpha, -beta, and -delta during granulocyte-lineage specification." Proc Natl Acad Sci U S A 93(20): 10838-10843.Forster, R., E. Kremmer, A. Schubel, D. Breitfeld, A. Kleinschmidt, C. Nerl, G. Bernhardt and M. Lipp (1998). "Intracellular and surface expression of the HIV-1 coreceptor CXCR4/fusin on various leukocyte subsets: rapid internalization and recycling upon activation." J Immunol 160(3): 1522-1531.Fuchs, T. A., U. Abed, C. Goosmann, R. Hurwitz, I. Schulze, V. Wahn, Y. Weinrauch, V. Brinkmann and A. Zychlinsky (2007). "Novel cell death program leads to neutrophil extracellular traps." J Cell Biol 176(2): 231-241.Fulop, T., A. Larbi, N. Douziech, C. Fortin, K. P. Guerard, O. Lesur, A. Khalil and G. Dupuis (2004). "Signal transduction and functional changes in neutrophils with aging." Aging Cell 3(4): 217-226.Furze, R. C. and S. M. Rankin (2008). "The role of the bone marrow in neutrophil clearance under homeostatic conditions in the mouse." FASEB J 22(9): 3111-3119.Futami, M., Q. S. Zhu, Z. L. Whichard, L. Xia, Y. Ke, B. G. Neel, G. S. Feng and S. J. Corey (2011). "G-CSF receptor activation of the Src kinase Lyn is mediated by Gab2 recruitment of the Shp2 phosphatase." Blood 118(4): 1077-1086.Galbraith, P. R., L. S. Valberg and M. Brown (1965). "Patterns of Granulocyte Kinetics in Health, Infection and in Carcinoma." Blood 25: 683-692.Gavazzi, G. and K. H. Krause (2002). "Ageing and infection." Lancet Infect Dis 2(11): 659-666.Geiger, H., G. de Haan and M. C. Florian (2013). "The ageing haematopoietic stem cell compartment." Nature Reviews Immunology 13(5): 376-389.Geiger, H., G. de Haan and M. C. Florian (2013). "The ageing haematopoietic stem cell compartment." Nat Rev Immunol 13(5): 376-389.Giladi, A., F. Paul, Y. Herzog, Y. Lubling, A. Weiner, I. Yofe, D. Jaitin, N. Cabezas-Wallscheid, R. Dress, F. Ginhoux, A. Trumpp, A. Tanay and I. Amit (2018). "Single-cell characterization of haematopoietic progenitors and their trajectories in homeostasis and perturbed haematopoiesis." Nat Cell Biol 20(7): 836-846.Gilks, C. B., S. E. Bear, H. L. Grimes and P. N. Tsichlis (1993). "Progression of interleukin-2 (IL-2)-dependent rat T cell lymphoma lines to IL-2-independent growth following activation of a gene (Gfi-1) encoding a novel zinc finger protein." Mol Cell Biol 13(3): 1759-1768.Golde, D. W. and M. J. Cline (1974). "Regulation of granulopoiesis." N Engl J Med 291(26): 1388-1395.Gombart, A. F., S. H. Kwok, K. L. Anderson, Y. Yamaguchi, B. E. Torbett and H. P. Koeffler (2003). "Regulation of neutrophil and eosinophil secondary granule gene expression by transcription factors C/EBP epsilon and PU.1." Blood 101(8): 3265-3273.Gombart, A. F., M. Shiohara, S. H. Kwok, K. Agematsu, A. Komiyama and H. P. Koeffler (2001). "Neutrophil-specific granule deficiency: homozygous recessive inheritance of a frameshift mutation in the gene encoding transcription factor CCAAT/enhancer binding protein--epsilon." Blood 97(9): 2561-2567.Grassi, L., F. Pourfarzad, S. Ullrich, A. Merkel, F. Were, E. Carrillo-de-Santa-Pau, G. Yi, I. H. Hiemstra, A. T. J. Tool, E. Mul, J. Perner, E. Janssen-Megens, K. Berentsen, H. Kerstens, E. Habibi, M. Gut, M. L. Yaspo, M. Linser, E. Lowy, A. Datta, L. Clarke, P. Flicek, M. Vingron, D. Roos, T. K. van den Berg, S. Heath, D. Rico, M. Frontini, M. Kostadima, I. Gut, A. Valencia, W. H. Ouwehand, H. G. Stunnenberg, J. H. A. Martens and T. W. Kuijpers (2018). "Dynamics of Transcription Regulation in Human Bone Marrow Myeloid Differentiation to Mature Blood Neutrophils." Cell Rep 24(10): 2784-2794.Graves, B. J., P. F. Johnson and S. L. McKnight (1986). "Homologous recognition of a promoter domain common to the MSV LTR and the HSV tk gene." Cell 44(4): 565-576.Grieshaber-Bouyer, R., F. A. Radtke, P. Cunin, G. Stifano, A. Levescot, B. Vijaykumar, N. Nelson-Maney, R. B. Blaustein, P. A. Monach, P. A. Nigrovic and C. ImmGen (2021). "The neutrotime transcriptional signature defines a single continuum of neutrophils across biological compartments." Nat Commun 12(1): 2856.Grimes, H. L., T. O. Chan, P. A. Zweidler-McKay, B. Tong and P. N. Tsichlis (1996). "The Gfi-1 proto-oncoprotein contains a novel transcriptional repressor domain, SNAG, and inhibits G1 arrest induced by interleukin-2 withdrawal." Mol Cell Biol 16(11): 6263-6272.Guma, M., L. Ronacher, R. Liu-Bryan, S. Takai, M. Karin and M. Corr (2009). "Caspase 1-independent activation of interleukin-1beta in neutrophil-predominant inflammation." Arthritis Rheum 60(12): 3642-3650.Guo, H., O. Ma, N. A. Speck and A. D. Friedman (2012). "Runx1 deletion or dominant inhibition reduces Cebpa transcription via conserved promoter and distal enhancer sites to favor monopoiesis over granulopoiesis." Blood 119(19): 4408-4418.Gurol, T., W. Zhou and Q. Deng (2016). "MicroRNAs in neutrophils: potential next generation therapeutics for inflammatory ailments." Immunol Rev 273(1): 29-47.Hager, M., C. C. Pedersen, M. T. Larsen, M. K. Andersen, C. Hother, K. Gronbaek, H. Jarmer, N. Borregaard and J. B. Cowland (2011). "MicroRNA-130a-mediated down-regulation of Smad4 contributes to reduced sensitivity to TGF-beta1 stimulation in granulocytic precursors." Blood 118(25): 6649-6659.Hashimshony, T., F. Wagner, N. Sher and I. Yanai (2012). "CEL-Seq: single-cell RNA-Seq by multiplexed linear amplification." Cell Rep 2(3): 666-673.He, Z., C. Allers, C. Sugimoto, N. Ahmed, H. Fujioka, W. K. Kim, E. S. Didier and M. J. Kuroda (2018). "Rapid Turnover and High Production Rate of Myeloid Cells in Adult Rhesus Macaques with Compensations during Aging." J Immunol 200(12): 4059-4067.He, Z., M. D. Fahlberg, N. Takahashi, N. Slisarenko, N. Rout, E. S. Didier and M. J. Kuroda (2021). "Declining neutrophil production despite increasing G-CSF levels is associated with chronic inflammation in elderly rhesus macaques." J Leukoc Biol 109(6): 1033-1043.Heath, V., H. C. Suh, M. Holman, K. Renn, J. M. Gooya, S. Parkin, K. D. Klarmann, M. Ortiz, P. Johnson and J. Keller (2004). "C/EBPalpha deficiency results in hyperproliferation of hematopoietic progenitor cells and disrupts macrophage development in vitro and in vivo." Blood 104(6): 1639-1647.Helbling, P. M., E. Pineiro-Yanez, R. Gerosa, S. Boettcher, F. Al-Shahrour, M. G. Manz and C. Nombela-Arrieta (2019). "Global Transcriptomic Profiling of the Bone Marrow Stromal Microenvironment during Postnatal Development, Aging, and Inflammation." Cell Rep 29(10): 3313-3330 e3314.Henderson, R. B., L. H. Lim, P. A. Tessier, F. N. Gavins, M. Mathies, M. Perretti and N. Hogg (2001). "The use of lymphocyte function-associated antigen (LFA)-1-deficient mice to determine the role of LFA-1, Mac-1, and alpha4 integrin in the inflammatory response of neutrophils." J Exp Med 194(2): 219-226.Henry, R. M., A. D. Hoppe, N. Joshi and J. A. Swanson (2004). "The uniformity of phagosome maturation in macrophages." J Cell Biol 164(2): 185-194.Hernandez, P. A., R. J. Gorlin, J. N. Lukens, S. Taniuchi, J. Bohinjec, F. Francois, M. E. Klotman and G. A. Diaz (2003). "Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease." Nat Genet 34(1): 70-74.Hock, H., M. J. Hamblen, H. M. Rooke, D. Traver, R. T. Bronson, S. Cameron and S. H. Orkin (2003). "Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation." Immunity 18(1): 109-120.Hohaus, S., M. S. Petrovick, M. T. Voso, Z. Sun, D. E. Zhang and D. G. Tenen (1995). "PU.1 (Spi-1) and C/EBP alpha regulate expression of the granulocyte-macrophage colony-stimulating factor receptor alpha gene." Mol Cell Biol 15(10): 5830-5845.Honda, M. and P. Kubes (2018). "Neutrophils and neutrophil extracellular traps in the liver and gastrointestinal system." Nat Rev Gastroenterol Hepatol 15(4): 206-221.Hsieh, M. M., J. E. Everhart, D. D. Byrd-Holt, J. F. Tisdale and G. P. Rodgers (2007). "Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences." Ann Intern Med 146(7): 486-492.Hu, H., Y. R. Miao, L. H. Jia, Q. Y. Yu, Q. Zhang and A. Y. Guo (2019). "AnimalTFDB 3.0: a comprehensive resource for annotation and prediction of animal transcription factors." Nucleic Acids Res 47(D1): D33-D38.Islam, S., U. Kjallquist, A. Moliner, P. Zajac, J. B. Fan, P. Lonnerberg and S. Linnarsson (2011). "Characterization of the single-cell transcriptional landscape by highly multiplex RNA-seq." Genome Res 21(7): 1160-1167.Jacobsen, S. E. W. and C. Nerlov (2019). "Haematopoiesis in the era of advanced single-cell technologies." Nature Cell Biology 21(1): 2-8.Jacomy, M., T. Venturini, S. Heymann and M. Bastian (2014). "ForceAtlas2, a continuous graph layout algorithm for handy network visualization designed for the Gephi software." PLoS One 9(6): e98679.Jin, S., C. F. Guerrero-Juarez, L. Zhang, I. Chang, R. Ramos, C. H. Kuan, P. Myung, M. V. Plikus and Q. Nie (2021). "Inference and analysis of cell-cell communication using CellChat." Nat Commun 12(1): 1088.Johnnidis, J. B., M. H. Harris, R. T. Wheeler, S. Stehling-Sun, M. H. Lam, O. Kirak, T. R. Brummelkamp, M. D. Fleming and F. D. Camargo (2008). "Regulation of progenitor cell proliferation and granulocyte function by microRNA-223." Nature 451(7182): 1125-1129.Johnson, P. F., W. H. Landschulz, B. J. Graves and S. L. McKnight (1987). "Identification of a rat liver nuclear protein that binds to the enhancer core element of three animal viruses." Genes Dev 1(2): 133-146.Johnston, B. and P. Kubes (1999). "The alpha4-integrin: an alternative pathway for neutrophil recruitment?" Immunol Today 20(12): 545-550.Kalisky, T. and S. R. Quake (2011). "Single-cell genomics." Nat Methods 8(4): 311-314.Karsunky, H., H. Zeng, T. Schmidt, B. Zevnik, R. Kluge, K. W. Schmid, U. Duhrsen and T. Moroy (2002). "Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1." Nat Genet 30(3): 295-300.Katzerke, C., V. Madan, D. Gerloff, D. Brauer-Hartmann, J. U. Hartmann, A. A. Wurm, C. Muller-Tidow, S. Schnittger, D. G. Tenen, D. Niederwieser and G. Behre (2013). "Transcription factor C/EBPalpha-induced microRNA-30c inactivates Notch1 during granulopoiesis and is downregulated in acute myeloid leukemia." Blood 122(14): 2433-2442.Kawakami, M., H. Tsutsumi, T. Kumakawa, H. Abe, M. Hirai, S. Kurosawa, M. Mori and M. Fukushima (1990). "Levels of serum granulocyte colony-stimulating factor in patients with infections." Blood 76(10): 1962-1964.Kenny, E. F., A. Herzig, R. Kruger, A. Muth, S. Mondal, P. R. Thompson, V. Brinkmann, H. V. Bernuth and A. Zychlinsky (2017). "Diverse stimuli engage different neutrophil extracellular trap pathways." Elife 6.Kerrigan, A. M. and G. D. Brown (2009). "C-type lectins and phagocytosis." Immunobiology 214(7): 562-575.Kienle, K., K. M. Glaser, S. Eickhoff, M. Mihlan, K. Knopper, E. Reategui, M. W. Epple, M. Gunzer, R. Baumeister, T. K. Tarrant, R. N. Germain, D. Irimia, W. Kastenmuller and T. Lammermann (2021). "Neutrophils self-limit swarming to contain bacterial growth in vivo." Science 372(6548).Kienle, K. and T. Lammermann (2016). "Neutrophil swarming: an essential process of the neutrophil tissue response." Immunol Rev 273(1): 76-93.Kim, H. O., H. S. Kim, J. C. Youn, E. C. Shin and S. Park (2011). "Serum cytokine profiles in healthy young and elderly population assessed using multiplexed bead-based immunoassays." J Transl Med 9: 113.Kim, M. H., D. Yang, M. Kim, S. Y. Kim, D. Kim and S. J. Kang (2017). "A late-lineage murine neutrophil precursor population exhibits dynamic changes during demand-adapted granulopoiesis." Sci Rep 7: 39804.Klein, A. M., L. Mazutis, I. Akartuna, N. Tallapragada, A. Veres, V. Li, L. Peshkin, D. A. Weitz and M. W. Kirschner (2015). "Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells." Cell 161(5): 1187-1201.Klein, C. (2011). "Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes." Annu Rev Immunol 29: 399-413.Kolaczkowska, E. and P. Kubes (2013). "Neutrophil recruitment and function in health and inflammation." Nat Rev Immunol 13(3): 159-175.Kozomara, A., M. Birgaoanu and S. Griffiths-Jones (2019). "miRBase: from microRNA sequences to function." Nucleic Acids Res 47(D1): D155-D162.Krishnarajah, S., F. Ingelfinger, E. Friebel, D. Cansever, A. Amorim, M. Andreadou, D. Bamert, G. Litscher, M. Lutz, M. Mayoux, S. Mundt, F. Ridder, C. Sparano, S. A. Stifter, C. Ulutekin, S. Unger, M. Vermeer, P. Zwicky, M. Greter, S. Tugues, D. De Feo and B. Becher (2021). "Single-cell profiling of immune system alterations in lymphoid, barrier and solid tissues in aged mice." Nature Aging.Kulkarni, U., R. L. Zemans, C. A. Smith, S. C. Wood, J. C. Deng and D. R. Goldstein (2019). "Excessive neutrophil levels in the lung underlie the age-associated increase in influenza mortality." Mucosal Immunol 12(2): 545-554.Kwok, I., E. Becht, Y. Xia, M. Ng, Y. C. Teh, L. Tan, M. Evrard, J. L. Y. Li, H. T. N. Tran, Y. Tan, D. Liu, A. Mishra, K. H. Liong, K. Leong, Y. Zhang, A. Olsson, C. K. Mantri, P. Shyamsunder, Z. Liu, C. Piot, C. A. Dutertre, H. Cheng, S. Bari, N. Ang, S. K. Biswas, H. P. Koeffler, H. L. Tey, A. Larbi, I. H. Su, B. Lee, A. St John, J. K. Y. Chan, W. Y. K. Hwang, J. Chen, N. Salomonis, S. Z. Chong, H. L. Grimes, B. Liu, A. Hidalgo, E. W. Newell, T. Cheng, F. Ginhoux and L. G. Ng (2020). "Combinatorial Single-Cell Analyses of Granulocyte-Monocyte Progenitor Heterogeneity Reveals an Early Uni-potent Neutrophil Progenitor." Immunity 53(2): 303-318 e305.La Manno, G., R. Soldatov, A. Zeisel, E. Braun, H. Hochgerner, V. Petukhov, K. Lidschreiber, M. E. Kastriti, P. Lonnerberg, A. Furlan, J. Fan, L. E. Borm, Z. Liu, D. van Bruggen, J. Guo, X. He, R. Barker, E. Sundstrom, G. Castelo-Branco, P. Cramer, I. Adameyko, S. Linnarsson and P. V. Kharchenko (2018). "RNA velocity of single cells." Nature 560(7719): 494-498.Lahoz-Beneytez, J., M. Elemans, Y. Zhang, R. Ahmed, A. Salam, M. Block, C. Niederalt, B. Asquith and D. Macallan (2016). "Human neutrophil kinetics: modeling of stable isotope labeling data supports short blood neutrophil half-lives." Blood 127(26): 3431-3438.Lammermann, T., P. V. Afonso, B. R. Angermann, J. M. Wang, W. Kastenmuller, C. A. Parent and R. N. Germain (2013). "Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo." Nature 498(7454): 371-375.Lange, M., V. Bergen, M. Klein, M. Setty, B. Reuter, M. Bakhti, H. Lickert, M. Ansari, J. Schniering, H. B. Schiller, D. Pe’er and F. J. Theis (2020). "CellRank for directed single-cell fate mapping." bioRxiv: 2020.2010.2019.345983.Larsen, M. T., M. Hager, A. Glenthoj, F. Asmar, S. N. Clemmensen, H. Mora-Jensen, N. Borregaard and J. B. Cowland (2014). "miRNA-130a regulates C/EBP-epsilon expression during granulopoiesis." Blood 123(7): 1079-1089.Larsen, M. T., C. Hother, M. Hager, C. C. Pedersen, K. Theilgaard-Monch, N. Borregaard and J. B. Cowland (2013). "MicroRNA profiling in human neutrophils during bone marrow granulopoiesis and in vivo exudation." PLoS One 8(3): e58454.Lee, W. Y. and P. Kubes (2008). "Leukocyte adhesion in the liver: distinct adhesion paradigm from other organs." J Hepatol 48(3): 504-512.Leiding, J. W. (2017). "Neutrophil Evolution and Their Diseases in Humans." Front Immunol 8: 1009.Leite Pereira, A., S. Bitoun, A. Paoletti, G. Nocturne, E. Marcos Lopez, A. Cosma, R. Le Grand, X. Mariette and N. Tchitchek (2019). "Characterization of Phenotypes and Functional Activities of Leukocytes From Rheumatoid Arthritis Patients by Mass Cytometry." Front Immunol 10: 2384.Lekstrom-Himes, J. and K. G. Xanthopoulos (1999). "CCAAT/enhancer binding protein epsilon is critical for effective neutrophil-mediated response to inflammatory challenge." Blood 93(9): 3096-3105.Lekstrom-Himes, J. A., S. E. Dorman, P. Kopar, S. M. Holland and J. I. Gallin (1999). "Neutrophil-specific granule deficiency results from a novel mutation with loss of function of the transcription factor CCAAT/enhancer binding protein epsilon." J Exp Med 189(11): 1847-1852.Leliefeld, P. H., L. Koenderman and J. Pillay (2015). "How Neutrophils Shape Adaptive Immune Responses." Front Immunol 6: 471.Lemaitre, J., A. Cosma, D. Desjardins, O. Lambotte and R. Le Grand (2020). "Mass Cytometry Reveals the Immaturity of Circulating Neutrophils during SIV Infection." J Innate Immun 12(2): 170-181.Li, P., M. Li, M. R. Lindberg, M. J. Kennett, N. Xiong and Y. Wang (2010). "PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps." J Exp Med 207(9): 1853-1862.Li, X., X. Zeng, Y. Xu, B. Wang, Y. Zhao, X. Lai, P. Qian and H. Huang (2020). "Mechanisms and rejuvenation strategies for aged hematopoietic stem cells." J Hematol Oncol 13(1): 31.Lieschke, G. J., D. Grail, G. Hodgson, D. Metcalf, E. Stanley, C. Cheers, K. J. Fowler, S. Basu, Y. F. Zhan and A. R. Dunn (1994). "Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization." Blood 84(6): 1737-1746.Lin, F. T., O. A. MacDougald, A. M. Diehl and M. D. Lane (1993). "A 30-kDa alternative translation product of the CCAAT/enhancer binding protein alpha message: transcriptional activator lacking antimitotic activity." Proc Natl Acad Sci U S A 90(20): 9606-9610.Lin, L. I., C. Y. Chen, D. T. Lin, W. Tsay, J. L. Tang, Y. C. Yeh, H. L. Shen, F. H. Su, M. Yao, S. Y. Huang and H. F. Tien (2005). "Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells." Clin Cancer Res 11(4): 1372-1379.Liu, F., H. Y. Wu, R. Wesselschmidt, T. Kornaga and D. C. Link (1996). "Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice." Immunity 5(5): 491-501.Loetscher, M., T. Geiser, T. O'Reilly, R. Zwahlen, M. Baggiolini and B. Moser (1994). "Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes." J Biol Chem 269(1): 232-237.Lopez-Otin, C., M. A. Blasco, L. Partridge, M. Serrano and G. Kroemer (2013). "The Hallmarks of Aging." Cell 153(6): 1194-1217.Lord, J. M., S. Butcher, V. Killampali, D. Lascelles and M. Salmon (2001). "Neutrophil ageing and immunesenescence." Mech Ageing Dev 122(14): 1521-1535.Lu, R. J., S. Taylor, K. Contrepois, M. Kim, J. I. Bravo, M. Ellenberger, N. K. Sampathkumar and B. A. Benayoun (2021). "Multi-omic profiling of primary mouse neutrophils predicts a pattern of sex- and age-related functional regulation." Nature Aging.Luecken, M. D. and F. J. Theis (2019). "Current best practices in single-cell RNA-seq analysis: a tutorial." Mol Syst Biol 15(6): e8746.Luedde, T., M. Duderstadt, K. L. Streetz, F. Tacke, S. Kubicka, M. P. Manns and C. Trautwein (2004). "C/EBP beta isoforms LIP and LAP modulate progression of the cell cycle in the regenerating mouse liver." Hepatology 40(2): 356-365.Lun, A. T. L., S. Riesenfeld, T. Andrews, T. P. Dao, T. Gomes, J. participants in the 1st Human Cell Atlas and J. C. Marioni (2019). "EmptyDrops: distinguishing cells from empty droplets in droplet-based single-cell RNA sequencing data." Genome Biol 20(1): 63.Lunger, I., M. Fawaz and M. A. Rieger (2017). "Single-cell analyses to reveal hematopoietic stem cell fate decisions." Febs Letters 591(15): 2195-2212.Luo, H., L. He, G. Zhang, J. Yu, Y. Chen, H. Yin, H. Goyal, G. M. Zhang, Y. Xiao, C. Gu, M. Yin, X. Jiang, X. Song and L. Zhang (2019). "Normal Reference Intervals of Neutrophil-To-Lymphocyte Ratio, Platelet-To-Lymphocyte Ratio, Lymphocyte-To-Monocyte Ratio, and Systemic Immune Inflammation Index in Healthy Adults: a Large Multi-Center Study from Western China." Clin Lab 65(3).Ma, Q., D. Jones and T. A. Springer (1999). "The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment." Immunity 10(4): 463-471.Macosko, E. Z., A. Basu, R. Satija, J. Nemesh, K. Shekhar, M. Goldman, I. Tirosh, A. R. Bialas, N. Kamitaki, E. M. Martersteck, J. J. Trombetta, D. A. Weitz, J. R. Sanes, A. K. Shalek, A. Regev and S. A. McCarroll (2015). "Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets." Cell 161(5): 1202-1214.Mantovani, A., M. A. Cassatella, C. Costantini and S. Jaillon (2011). "Neutrophils in the activation and regulation of innate and adaptive immunity." Nat Rev Immunol 11(8): 519-531.Manz, M. G. and S. Boettcher (2014). "Emergency granulopoiesis." Nature Reviews Immunology 14(5): 302-314.Margraf, A., K. Ley and A. Zarbock (2019). "Neutrophil Recruitment: From Model Systems to Tissue-Specific Patterns." Trends Immunol 40(7): 613-634.Martin, C., P. C. Burdon, G. Bridger, J. C. Gutierrez-Ramos, T. J. Williams and S. M. Rankin (2003). "Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence." Immunity 19(4): 583-593.Mayadas, T. N., X. Cullere and C. A. Lowell (2014). "The multifaceted functions of neutrophils." Annu Rev Pathol 9: 181-218.McDonald, B. and P. Kubes (2011). "Cellular and molecular choreography of neutrophil recruitment to sites of sterile inflammation." J Mol Med (Berl) 89(11): 1079-1088.McDonald, B., E. F. McAvoy, F. Lam, V. Gill, C. de la Motte, R. C. Savani and P. Kubes (2008). "Interaction of CD44 and hyaluronan is the dominant mechanism for neutrophil sequestration in inflamed liver sinusoids." J Exp Med 205(4): 915-927.McGhee, L., J. Bryan, L. Elliott, H. L. Grimes, A. Kazanjian, J. N. Davis and S. Meyers (2003). "Gfi-1 attaches to the nuclear matrix, associates with ETO (MTG8) and histone deacetylase proteins, and represses transcription using a TSA-sensitive mechanism." J Cell Biochem 89(5): 1005-1018.Mermel, C. H., M. L. McLemore, F. Liu, S. Pereira, J. Woloszynek, C. A. Lowell and D. C. Link (2006). "Src family kinases are important negative regulators of G-CSF-dependent granulopoiesis." Blood 108(8): 2562-2568.Metcalf, D. (1980). "Clonal extinction of myelomonocytic leukemic cells by serum from mice injected with endotoxin." Int J Cancer 25(2): 225-233.Metcalf, D. and N. A. Nicola (1983). "Proliferative effects of purified granulocyte colony-stimulating factor (G-CSF) on normal mouse hemopoietic cells." J Cell Physiol 116(2): 198-206.Mizgerd, J. P., H. Kubo, G. J. Kutkoski, S. D. Bhagwan, K. Scharffetter-Kochanek, A. L. Beaudet and C. M. Doerschuk (1997). "Neutrophil emigration in the skin, lungs, and peritoneum: different requirements for CD11/CD18 revealed by CD18-deficient mice." J Exp Med 186(8): 1357-1364.Mizgerd, J. P., B. B. Meek, G. J. Kutkoski, D. C. Bullard, A. L. Beaudet and C. M. Doerschuk (1996). "Selectins and neutrophil traffic: margination and Streptococcus pneumoniae-induced emigration in murine lungs." J Exp Med 184(2): 639-645.Mocsai, A. (2013). "Diverse novel functions of neutrophils in immunity, inflammation, and beyond." J Exp Med 210(7): 1283-1299.Mollaoglu, G., A. Jones, S. J. Wait, A. Mukhopadhyay, S. Jeong, R. Arya, S. A. Camolotto, T. L. Mosbruger, C. J. Stubben, C. J. Conley, A. Bhutkar, J. M. Vahrenkamp, K. C. Berrett, M. H. Cessna, T. E. Lane, B. L. Witt, M. E. Salama, J. Gertz, K. B. Jones, E. L. Snyder and T. G. Oliver (2018). "The Lineage-Defining Transcription Factors SOX2 and NKX2-1 Determine Lung Cancer Cell Fate and Shape the Tumor Immune Microenvironment." Immunity 49(4): 764-779 e769.Monaco, G., B. Lee, W. Xu, S. Mustafah, Y. Y. Hwang, C. Carre, N. Burdin, L. Visan, M. Ceccarelli, M. Poidinger, A. Zippelius, J. Pedro de Magalhaes and A. Larbi (2019). "RNA-Seq Signatures Normalized by mRNA Abundance Allow Absolute Deconvolution of Human Immune Cell Types." Cell Rep 26(6): 1627-1640 e1627.Montecino-Rodriguez, E., B. Berent-Maoz and K. Dorshkind (2013). "Causes, consequences, and reversal of immune system aging." J Clin Invest 123(3): 958-965.Montoya-Durango, D. E., C. S. Velu, A. Kazanjian, M. E. Rojas, C. M. Jay, G. D. Longmore and H. L. Grimes (2008). "Ajuba functions as a histone deacetylase-dependent co-repressor for autoregulation of the growth factor-independent-1 transcription factor." J Biol Chem 283(46): 32056-32065.Morosetti, R., D. J. Park, A. M. Chumakov, I. Grillier, M. Shiohara, A. F. Gombart, T. Nakamaki, K. Weinberg and H. P. Koeffler (1997). "A novel, myeloid transcription factor, C/EBP epsilon, is upregulated during granulocytic, but not monocytic, differentiation." Blood 90(7): 2591-2600.Morstyn, G., L. Campbell, L. M. Souza, N. K. Alton, J. Keech, M. Green, W. Sheridan, D. Metcalf and R. Fox (1988). "Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy." Lancet 1(8587): 667-672.Muench, D. E., A. Olsson, K. Ferchen, G. Pham, R. A. Serafin, S. Chutipongtanate, P. Dwivedi, B. Song, S. Hay, K. Chetal, L. R. Trump-Durbin, J. Mookerjee-Basu, K. Zhang, J. C. Yu, C. Lutzko, K. C. Myers, K. L. Nazor, K. D. Greis, D. J. Kappes, S. S. Way, N. Salomonis and H. L. Grimes (2020). "Mouse models of neutropenia reveal progenitor-stage-specific defects." Nature 582(7810): 109-114.Muller, C., A. Bremer, S. Schreiber, S. Eichwald and C. F. Calkhoven (2010). "Nucleolar retention of a translational C/EBPalpha isoform stimulates rDNA transcription and cell size." EMBO J 29(5): 897-909.Nagase, H., M. Miyamasu, M. Yamaguchi, M. Imanishi, N. H. Tsuno, K. Matsushima, K. Yamamoto, Y. Morita and K. Hirai (2002). "Cytokine-mediated regulation of CXCR4 expression in human neutrophils." J Leukoc Biol 71(4): 711-717.Nauseef, W. M. (2007). "How human neutrophils kill and degrade microbes: an integrated view." Immunol Rev 219: 88-102.Neeli, I., S. N. Khan and M. Radic (2008). "Histone deimination as a response to inflammatory stimuli in neutrophils." J Immunol 180(3): 1895-1902.Nemeth, T., M. Sperandio and A. Mocsai (2020). "Neutrophils as emerging therapeutic targets." Nature Reviews Drug Discovery.Nerlov, C. (2007). "The C/EBP family of transcription factors: a paradigm for interaction between gene expression and proliferation control." Trends Cell Biol 17(7): 318-324.Nestorowa, S., F. K. Hamey, B. Pijuan Sala, E. Diamanti, M. Shepherd, E. Laurenti, N. K. Wilson, D. G. Kent and B. Gottgens (2016). "A single-cell resolution map of mouse hematopoietic stem and progenitor cell differentiation." Blood 128(8): e20-31.Ng, L. G., R. Ostuni and A. Hidalgo (2019). "Heterogeneity of neutrophils." Nature Reviews Immunology 19(4): 255-265.Nicola, N. A., C. G. Begley and D. Metcalf (1985). "Identification of the human analogue of a regulator that induces differentiation in murine leukaemic cells." Nature 314(6012): 625-628.Nicola, N. A., D. Metcalf, M. Matsumoto and G. R. Johnson (1983). "Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells. Identification as granulocyte colony-stimulating factor." J Biol Chem 258(14): 9017-9023.Nicola, N. A. and L. Peterson (1986). "Identification of distinct receptors for two hemopoietic growth factors (granulocyte colony-stimulating factor and multipotential colony-stimulating factor) by chemical cross-linking." J Biol Chem 261(26): 12384-12389.Nikolich-Zugich, J. (2018). "The twilight of immunity: emerging concepts in aging of the immune system." Nat Immunol 19(1): 10-19.Nomellini, V., A. L. Brubaker, S. Mahbub, J. L. Palmer, C. R. Gomez and E. J. Kovacs (2012). "Dysregulation of neutrophil CXCR2 and pulmonary endothelial icam-1 promotes age-related pulmonary inflammation." Aging Dis 3(3): 234-247.Nordenfelt, P. and H. Tapper (2011). "Phagosome dynamics during phagocytosis by neutrophils." J Leukoc Biol 90(2): 271-284.Oelgeschlager, M., I. Nuchprayoon, B. Luscher and A. D. Friedman (1996). "C/EBP, c-Myb, and PU.1 cooperate to regulate the neutrophil elastase promoter." Mol Cell Biol 16(9): 4717-4725.Olsson, A., M. Venkatasubramanian, V. K. Chaudhri, B. J. Aronow, N. Salomonis, H. Singh and H. L. Grimes (2016). "Single-cell analysis of mixed-lineage states leading to a binary cell fate choice." Nature 537(7622): 698-+.Ordonez-Rueda, D., F. Jonsson, D. A. Mancardi, W. Zhao, A. Malzac, Y. Liang, E. Bertosio, P. Grenot, V. Blanquet, S. Sabrautzki, M. H. de Angelis, S. Meresse, E. Duprez, P. Bruhns, B. Malissen and M. Malissen (2012). "A hypomorphic mutation in the Gfi1 transcriptional repressor results in a novel form of neutropenia." Eur J Immunol 42(9): 2395-2408.Osada, S., H. Yamamoto, T. Nishihara and M. Imagawa (1996). "DNA binding specificity of the CCAAT/enhancer-binding protein transcription factor family." J Biol Chem 271(7): 3891-3896.Pabst, T., B. U. Mueller, P. Zhang, H. S. Radomska, S. Narravula, S. Schnittger, G. Behre, W. Hiddemann and D. G. Tenen (2001). "Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia." Nat Genet 27(3): 263-270.Pan, H. and J. E. Shively (2010). "Carcinoembryonic antigen-related cell adhesion molecule-1 regulates granulopoiesis by inhibition of granulocyte colony-stimulating factor receptor." Immunity 33(4): 620-631.Panopoulos, A. D. and S. S. Watowich (2008). "Granulocyte colony-stimulating factor: molecular mechanisms of action during steady state and 'emergency' hematopoiesis." Cytokine 42(3): 277-288.Patel, L., S. J. Charlton, J. K. Chambers and C. H. Macphee (2001). "Expression and functional analysis of chemokine receptors in human peripheral blood leukocyte populations." Cytokine 14(1): 27-36.Person, R. E., F. Q. Li, Z. Duan, K. F. Benson, J. Wechsler, H. A. Papadaki, G. Eliopoulos, C. Kaufman, S. J. Bertolone, B. Nakamoto, T. Papayannopoulou, H. L. Grimes and M. Horwitz (2003). "Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2." Nat Genet 34(3): 308-312.Phillipson, M., B. Heit, P. Colarusso, L. Liu, C. M. Ballantyne and P. Kubes (2006). "Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade." J Exp Med 203(12): 2569-2575.Picelli, S., A. K. Bjorklund, O. R. Faridani, S. Sagasser, G. Winberg and R. Sandberg (2013). "Smart-seq2 for sensitive full-length transcriptome profiling in single cells." Nat Methods 10(11): 1096-1098.Pollenus, E., B. Malengier-Devlies, L. Vandermosten, T. T. Pham, T. Mitera, H. Possemiers, L. Boon, G. Opdenakker, P. Matthys and P. E. Van den Steen (2019). "Limitations of neutrophil depletion by anti-Ly6G antibodies in two heterogenic immunological models." Immunol Lett 212: 30-36.Priam, P., V. Krasteva, P. Rousseau, G. D'Angelo, L. Gaboury, G. Sauvageau and J. A. Lessard (2017). "SMARCD2 subunit of SWI/SNF chromatin-remodeling complexes mediates granulopoiesis through a CEBPvarepsilon dependent mechanism." Nat Genet 49(5): 753-764.Price, T. H., G. S. Chatta and D. C. Dale (1996). "Effect of recombinant granulocyte colony-stimulating factor on neutrophil kinetics in normal young and elderly humans." Blood 88(1): 335-340.Pulikkan, J. A., P. S. Peramangalam, V. Dengler, P. A. Ho, C. Preudhomme, S. Meshinchi, M. Christopeit, O. Nibourel, C. Muller-Tidow, S. K. Bohlander, D. G. Tenen and G. Behre (2010). "C/EBPalpha regulated microRNA-34a targets E2F3 during granulopoiesis and is down-regulated in AML with CEBPA mutations." Blood 116(25): 5638-5649.Puttur, F., L. Denney, L. G. Gregory, J. Vuononvirta, R. Oliver, L. J. Entwistle, S. A. Walker, M. B. Headley, E. J. McGhee, J. E. Pease, M. F. Krummel, L. M. Carlin and C. M. Lloyd (2019). "Pulmonary environmental cues drive group 2 innate lymphoid cell dynamics in mice and humans." Sci Immunol 4(36).Qian, F., X. Guo, X. Wang, X. Yuan, S. Chen, S. E. Malawista, L. K. Bockenstedt, H. G. Allore and R. R. Montgomery (2014). "Reduced bioenergetics and toll-like receptor 1 function in human polymorphonuclear leukocytes in aging." Aging (Albany NY) 6(2): 131-139.Qin, Y., L. Wu, Y. Ouyang, P. Zhou, H. Zhou, Y. Wang, J. Ma, J. Zhang, Y. Chen, J. Qian, Y. Tang and N. Shen (2017). "MiR-125a Is a critical modulator for neutrophil development." PLoS Genet 13(10): e1007027.Radomska, H. S., C. S. Huettner, P. Zhang, T. Cheng, D. T. Scadden and D. G. Tenen (1998). "CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors." Mol Cell Biol 18(7): 4301-4314.Ramji, D. P. and P. Foka (2002). "CCAAT/enhancer-binding proteins: structure, function and regulation." Biochem J 365(Pt 3): 561-575.Regev, A., S. A. Teichmann, E. S. Lander, I. Amit, C. Benoist, E. Birney, B. Bodenmiller, P. Campbell, P. Carninci, M. Clatworthy, H. Clevers, B. Deplancke, I. Dunham, J. Eberwine, R. Eils, W. Enard, A. Farmer, L. Fugger, B. Gottgens, N. Hacohen, M. Haniffa, M. Hemberg, S. Kim, P. Klenerman, A. Kriegstein, E. Lein, S. Linnarsson, E. Lundberg, J. Lundeberg, P. Majumder, J. C. Marioni, M. Merad, M. Mhlanga, M. Nawijn, M. Netea, G. Nolan, D. Pe'er, A. Phillipakis, C. P. Ponting, S. Quake, W. Reik, O. Rozenblatt-Rosen, J. Sanes, R. Satija, T. N. Schumacher, A. Shalek, E. Shapiro, P. Sharma, J. W. Shin, O. Stegle, M. Stratton, M. J. T. Stubbington, F. J. Theis, M. Uhlen, A. van Oudenaarden, A. Wagner, F. Watt, J. Weissman, B. Wold, R. Xavier, N. Yosef and P. Human Cell Atlas Meeting (2017). "The Human Cell Atlas." Elife 6.Renshaw, M., J. Rockwell, C. Engleman, A. Gewirtz, J. Katz and S. Sambhara (2002). "Cutting edge: impaired Toll-like receptor expression and function in aging." J Immunol 169(9): 4697-4701.Reutershan, J., M. A. Morris, T. L. Burcin, D. F. Smith, D. Chang, M. S. Saprito and K. Ley (2006). "Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung." J Clin Invest 116(3): 695-702.Rodrigues, L. P., V. R. Teixeira, T. Alencar-Silva, B. Simonassi-Paiva, R. W. Pereira, R. Pogue and J. L. Carvalho (2021). "Hallmarks of aging and immunosenescence: Connecting the dots." Cytokine Growth Factor Rev 59: 9-21.Rohrbach, A. S., D. J. Slade, P. R. Thompson and K. A. Mowen (2012). "Activation of PAD4 in NET formation." Front Immunol 3: 360.Ron, D. and J. F. Habener (1992). "CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription." Genes Dev 6(3): 439-453.Rorvig, S., O. Ostergaard, N. H. Heegaard and N. Borregaard (2013). "Proteome profiling of human neutrophil granule subsets, secretory vesicles, and cell membrane: correlation with transcriptome profiling of neutrophil precursors." J Leukoc Biol 94(4): 711-721.Ross, S. E., H. S. Radomska, B. Wu, P. Zhang, J. N. Winnay, L. Bajnok, W. S. Wright, F. Schaufele, D. G. Tenen and O. A. MacDougald (2004). "Phosphorylation of C/EBPalpha inhibits granulopoiesis." Mol Cell Biol 24(2): 675-686.Rossaint, J. and A. Zarbock (2013). "Tissue-specific neutrophil recruitment into the lung, liver, and kidney." J Innate Immun 5(4): 348-357.Rossi, D. J., D. Bryder, J. M. Zahn, H. Ahlenius, R. Sonu, A. J. Wagers and I. L. Weissman (2005). "Cell intrinsic alterations underlie hematopoietic stem cell aging." Proc Natl Acad Sci U S A 102(26): 9194-9199.Saleque, S., J. Kim, H. M. Rooke and S. H. Orkin (2007). "Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1." Mol Cell 27(4): 562-572.Sapey, E., H. Greenwood, G. Walton, E. Mann, A. Love, N. Aaronson, R. H. Insall, R. A. Stockley and J. M. Lord (2014). "Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence." Blood 123(2): 239-248.Scapini, P., C. Laudanna, C. Pinardi, P. Allavena, A. Mantovani, S. Sozzani and M. A. Cassatella (2001). "Neutrophils produce biologically active macrophage inflammatory protein-3alpha (MIP-3alpha)/CCL20 and MIP-3beta/CCL19." Eur J Immunol 31(7): 1981-1988.Scheffold, A., A. H. Baig, Z. Chen, S. E. von Lohneysen, F. Becker, Y. Morita, A. I. Avila, M. Groth, A. Lechel, F. Schmid, J. M. Kraus, H. A. Kestler, S. Stilgenbauer, M. Philipp and M. D. Burkhalter (2020). "Elevated Hedgehog activity contributes to attenuated DNA damage responses in aged hematopoietic cells." Leukemia 34(4): 1125-1134.Schett, G., J. M. Dayer and B. Manger (2016). "Interleukin-1 function and role in rheumatic disease." Nat Rev Rheumatol 12(1): 14-24.Schroder, A. K. and L. Rink (2003). "Neutrophil immunity of the elderly." Mech Ageing Dev 124(4): 419-425.Scoazec, J. Y. and G. Feldmann (1994). "The cell adhesion molecules of hepatic sinusoidal endothelial cells." J Hepatol 20(2): 296-300.Scott, L. M., C. I. Civin, P. Rorth and A. D. Friedman (1992). "A novel temporal expression pattern of three C/EBP family members in differentiating myelomonocytic cells." Blood 80(7): 1725-1735.Segal, A. W. (2005). "How neutrophils kill microbes." Annual Review of Immunology 23: 197-223.Serwas, N. K., J. Huemer, R. Dieckmann, E. Mejstrikova, W. Garncarz, J. Litzman, B. Hoeger, O. Zapletal, A. Janda, K. L. Bennett, R. Kain, D. Kerjaschky and K. Boztug (2018). "CEBPE-Mutant Specific Granule Deficiency Correlates With Aberrant Granule Organization and Substantial Proteome Alterations in Neutrophils." Front Immunol 9: 588.Shaw, A. C., D. R. Goldstein and R. R. Montgomery (2013). "Age-dependent dysregulation of innate immunity." Nat Rev Immunol 13(12): 875-887.Shivdasani, R. A. (2006). "MicroRNAs: regulators of gene expression and cell differentiation." Blood 108(12): 3646-3653.Shyamsunder, P., H. Sankar, A. Mayakonda, L. Han, H. B. M. Nordin, T. W. Woon, M. Shanmugasundaram, P. Dakle, V. Madan and H. P. Koeffler (2018). "CARD10, a CEBPE target involved in granulocytic differentiation." Haematologica 103(8): 1269-1277.Skokowa, J., D. C. Dale, I. P. Touw, C. Zeidler and K. Welte (2017). "Severe congenital neutropenias." Nat Rev Dis Primers 3: 17032.Skokowa, J., M. Klimiankou, O. Klimenkova, D. Lan, K. Gupta, K. Hussein, E. Carrizosa, I. Kusnetsova, Z. Li, C. Sustmann, A. Ganser, C. Zeidler, H. H. Kreipe, J. Burkhardt, R. Grosschedl and K. Welte (2012). "Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis." Nat Med 18(10): 1550-1559.Skokowa, J., D. Lan, B. K. Thakur, F. Wang, K. Gupta, G. Cario, A. M. Brechlin, A. Schambach, L. Hinrichsen, G. Meyer, M. Gaestel, M. Stanulla, Q. Tong and K. Welte (2009). "NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD(+)-sirtuin-1-dependent pathway." Nat Med 15(2): 151-158.Solana, R., R. Tarazona, I. Gayoso, O. Lesur, G. Dupuis and T. Fulop (2012). "Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans." Semin Immunol 24(5): 331-341.Sorensen, O. E. and N. Borregaard (2016). "Neutrophil extracellular traps - the dark side of neutrophils." J Clin Invest 126(5): 1612-1620.Spitzer, M. H. and G. P. Nolan (2016). "Mass Cytometry: Single Cells, Many Features." Cell 165(4): 780-791.Stuart, T., A. Butler, P. Hoffman, C. Hafemeister, E. Papalexi, W. M. Mauck, 3rd, Y. Hao, M. Stoeckius, P. Smibert and R. Satija (2019). "Comprehensive Integration of Single-Cell Data." Cell 177(7): 1888-1902 e1821.Summers, C., S. M. Rankin, A. M. Condliffe, N. Singh, A. M. Peters and E. R. Chilvers (2010). "Neutrophil kinetics in health and disease." Trends Immunol 31(8): 318-324.Sun, D., M. Luo, M. Jeong, B. Rodriguez, Z. Xia, R. Hannah, H. Wang, T. Le, K. F. Faull, R. Chen, H. Gu, C. Bock, A. Meissner, B. Gottgens, G. J. Darlington, W. Li and M. A. Goodell (2014). "Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal." Cell Stem Cell 14(5): 673-688.Suratt, B. T., J. M. Petty, S. K. Young, K. C. Malcolm, J. G. Lieber, J. A. Nick, J. A. Gonzalo, P. M. Henson and G. S. Worthen (2004). "Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis." Blood 104(2): 565-571.Tabula Muris, C. (2020). "A single-cell transcriptomic atlas characterizes ageing tissues in the mouse." Nature 583(7817): 590-595.Tabula Muris, C., c. Overall, c. Logistical, c. Organ, processing, p. Library, sequencing, a. Computational data, a. Cell type, g. Writing, g. Supplemental text writing and i. Principal (2018). "Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris." Nature 562(7727): 367-372.Tamassia, N., F. Bianchetto-Aguilera, F. Arruda-Silva, E. Gardiman, S. Gasperini, F. Calzetti and M. A. Cassatella (2018). "Cytokine production by human neutrophils: Revisiting the "dark side of the moon"." Eur J Clin Invest 48 Suppl 2: e12952.Tang, F., C. Barbacioru, Y. Wang, E. Nordman, C. Lee, N. Xu, X. Wang, J. Bodeau, B. B. Tuch, A. Siddiqui, K. Lao and M. A. Surani (2009). "mRNA-Seq whole-transcriptome analysis of a single cell." Nat Methods 6(5): 377-382.Tecchio, C. and M. A. Cassatella (2016). "Neutrophil-derived chemokines on the road to immunity." Semin Immunol 28(2): 119-128.Tecchio, C., A. Micheletti and M. A. Cassatella (2014). "Neutrophil-derived cytokines: facts beyond expression." Front Immunol 5: 508.Terashima, T., D. English, J. C. Hogg and S. F. van Eeden (1998). "Release of polymorphonuclear leukocytes from the bone marrow by interleukin-8." Blood 92(3): 1062-1069.Theilgaard-Monch, K., L. C. Jacobsen, R. Borup, T. Rasmussen, M. D. Bjerregaard, F. C. Nielsen, J. B. Cowland and N. Borregaard (2005). "The transcriptional program of terminal granulocytic differentiation." Blood 105(4): 1785-1796.Tikhonova, A. N., I. Dolgalev, H. Hu, K. K. Sivaraj, E. Hoxha, A. Cuesta-Dominguez, S. Pinho, I. Akhmetzyanova, J. Gao, M. Witkowski, M. Guillamot, M. C. Gutkin, Y. Zhang, C. Marier, C. Diefenbach, S. Kousteni, A. Heguy, H. Zhong, D. R. Fooksman, J. M. Butler, A. Economides, P. S. Frenette, R. H. Adams, R. Satija, A. Tsirigos and I. Aifantis (2019). "The bone marrow microenvironment at single-cell resolution." Nature 569(7755): 222-228.Tomay, F., K. Wells, L. Duong, J. W. Tsu, D. E. Dye, H. G. Radley-Crabb, M. D. Grounds, T. Shavlakadze, P. Metharom, D. J. Nelson and C. Jackaman (2018). "Aged neutrophils accumulate in lymphoid tissues from healthy elderly mice and infiltrate T- and B-cell zones." Immunol Cell Biol 96(8): 831-840.Triot, A., P. M. Jarvinen, J. I. Arostegui, D. Murugan, N. Kohistani, J. L. Dapena Diaz, T. Racek, J. Puchalka, E. M. Gertz, A. A. Schaffer, D. Kotlarz, D. Pfeifer, C. Diaz de Heredia Rubio, M. A. Ozdemir, T. Patiroglu, M. Karakukcu, J. Sanchez de Toledo Codina, J. Yague, I. P. Touw, E. Unal and C. Klein (2014). "Inherited biallelic CSF3R mutations in severe congenital neutropenia." Blood 123(24): 3811-3817.Tsukada, J., Y. Yoshida, Y. Kominato and P. E. Auron (2011). "The CCAAT/enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation." Cytokine 54(1): 6-19.Ubeda, M., X. Z. Wang, H. Zinszner, I. Wu, J. F. Habener and D. Ron (1996). "Stress-induced binding of the transcriptional factor CHOP to a novel DNA control element." Mol Cell Biol 16(4): 1479-1489.Valente, S. A., W. F. Fallon, Jr., T. S. Alexander, E. R. Tomas, M. M. Evancho-Chapman, S. P. Schmidt, R. Gorski, O. Pizov, L. DeFine and A. J. Clark (2009). "Immunologic function in the elderly after injury--the neutrophil and innate immunity." J Trauma 67(5): 968-974.van Duin, D., S. Mohanty, V. Thomas, S. Ginter, R. R. Montgomery, E. Fikrig, H. G. Allore, R. Medzhitov and A. C. Shaw (2007). "Age-associated defect in human TLR-1/2 function." J Immunol 178(2): 970-975.van Raam, B. J., A. Drewniak, V. Groenewold, T. K. van den Berg and T. W. Kuijpers (2008). "Granulocyte colony-stimulating factor delays neutrophil apoptosis by inhibition of calpains upstream of caspase-3." Blood 112(5): 2046-2054.Velten, L., S. F. Haas, S. Raffel, S. Blaszkiewicz, S. Islam, B. P. Hennig, C. Hirche, C. Lutz, E. C. Buss, D. Nowak, T. Boch, W.-K. Hofmann, A. D. Ho, W. Huber, A. Trumpp, M. A. G. Essers and L. M. Steinmetz (2017). "Human haematopoietic stem cell lineage commitment is a continuous process." Nature Cell Biology 19(4): 271-+.Velu, C. S., A. M. Baktula and H. L. Grimes (2009). "Gfi1 regulates miR-21 and miR-196b to control myelopoiesis." Blood 113(19): 4720-4728.Verbeek, W., J. Lekstrom-Himes, D. J. Park, P. M. Dang, P. T. Vuong, S. Kawano, B. M. Babior, K. Xanthopoulos and H. P. Koeffler (1999). "Myeloid transcription factor C/EBPepsilon is involved in the positive regulation of lactoferrin gene expression in neutrophils." Blood 94(9): 3141-3150.Vian, L., M. Di Carlo, E. Pelosi, F. Fazi, S. Santoro, A. M. Cerio, A. Boe, V. Rotilio, M. Billi, S. Racanicchi, U. Testa, F. Grignani and C. Nervi (2014). "Transcriptional fine-tuning of microRNA-223 levels directs lineage choice of human hematopoietic progenitors." Cell Death Differ 21(2): 290-301.Villani, A. C., R. Satija, G. Reynolds, S. Sarkizova, K. Shekhar, J. Fletcher, M. Griesbeck, A. Butler, S. Zheng, S. Lazo, L. Jardine, D. Dixon, E. Stephenson, E. Nilsson, I. Grundberg, D. McDonald, A. Filby, W. Li, P. L. De Jager, O. Rozenblatt-Rosen, A. A. Lane, M. Haniffa, A. Regev and N. Hacohen (2017). "Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors." Science 356(6335).Volker Bergen, M. L., Stefan Peidli, F. Alexander Wolf, Fabian J. Theis (2019). "Generalizing RNA velocity to transient cell states through dynamical modeling." biorxiv.von Andrian, U. H., J. D. Chambers, E. L. Berg, S. A. Michie, D. A. Brown, D. Karolak, L. Ramezani, E. M. Berger, K. E. Arfors and E. C. Butcher (1993). "L-selectin mediates neutrophil rolling in inflamed venules through sialyl LewisX-dependent and -independent recognition pathways." Blood 82(1): 182-191.Wada, T., T. Akagi, M. Muraoka, T. Toma, K. Kaji, K. Agematsu, H. P. Koeffler, T. Yokota and A. Yachie (2015). "A Novel In-Frame Deletion in the Leucine Zipper Domain of C/EBPepsilon Leads to Neutrophil-Specific Granule Deficiency." J Immunol 195(1): 80-86.Waltman, L. and N. J. van Eck (2013). "A smart local moving algorithm for large-scale modularity-based community detection." European Physical Journal B 86(11).Wang, D., J. D'Costa, C. I. Civin and A. D. Friedman (2006). "C/EBPalpha directs monocytic commitment of primary myeloid progenitors." Blood 108(4): 1223-1229.Wang, N. D., M. J. Finegold, A. Bradley, C. N. Ou, S. V. Abdelsayed, M. D. Wilde, L. R. Taylor, D. R. Wilson and G. J. Darlington (1995). "Impaired energy homeostasis in C/EBP alpha knockout mice." Science 269(5227): 1108-1112.Wang, X., U. Ros, D. Agrawal, E. C. Keller, J. Slotta-Huspenina, V. Dill, B. Shen, R. Shi, T. Herold, C. Belka, R. Mishra, F. Bassermann, A. J. Garcia-Saez and P. J. Jost (2021). "MLKL promotes cellular differentiation in myeloid leukemia by facilitating the release of G-CSF." Cell Death Differ.Ward, A. C., M. H. Hermans, L. Smith, Y. M. van Aesch, A. M. Schelen, C. Antonissen and I. P. Touw (1999). "Tyrosine-dependent and -independent mechanisms of STAT3 activation by the human granulocyte colony-stimulating factor (G-CSF) receptor are differentially utilized depending on G-CSF concentration." Blood 93(1): 113-124.Ward, A. C., D. M. Loeb, A. A. Soede-Bobok, I. P. Touw and A. D. Friedman (2000). "Regulation of granulopoiesis by transcription factors and cytokine signals." Leukemia 14(6): 973-990.Ward, A. C., Y. M. van Aesch, J. Gits, A. M. Schelen, J. P. de Koning, D. van Leeuwen, M. H. Freedman and I. P. Touw (1999). "Novel point mutation in the extracellular domain of the granulocyte colony-stimulating factor (G-CSF) receptor in a case of severe congenital neutropenia hyporesponsive to G-CSF treatment." J Exp Med 190(4): 497-507.Wenisch, C., S. Patruta, F. Daxbock, R. Krause and W. Horl (2000). "Effect of age on human neutrophil function." J Leukoc Biol 67(1): 40-45.Wessels, I., J. Jansen, L. Rink and P. Uciechowski (2010). "Immunosenescence of polymorphonuclear neutrophils." ScientificWorldJournal 10: 145-160.Williams, G. T., C. A. Smith, E. Spooncer, T. M. Dexter and D. R. Taylor (1990). "Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis." Nature 343(6253): 76-79.Williams, M. R., V. Azcutia, G. Newton, P. Alcaide and F. W. Luscinskas (2011). "Emerging mechanisms of neutrophil recruitment across endothelium." Trends Immunol 32(10): 461-469.Williamson, E. A., H. N. Xu, A. F. Gombart, W. Verbeek, A. M. Chumakov, A. D. Friedman and H. P. Koeffler (1998). "Identification of transcriptional activation and repression domains in human CCAAT/enhancer-binding protein epsilon." J Biol Chem 273(24): 14796-14804.Witzel, M., D. Petersheim, Y. Fan, E. Bahrami, T. Racek, M. Rohlfs, J. Puchalka, C. Mertes, J. Gagneur, C. Ziegenhain, W. Enard, A. Stray-Pedersen, P. D. Arkwright, M. R. Abboud, V. Pazhakh, G. J. Lieschke, P. M. Krawitz, M. Dahlhoff, M. R. Schneider, E. Wolf, H. P. Horny, H. Schmidt, A. A. Schaffer and C. Klein (2017). "Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes." Nat Genet 49(5): 742-752.Wolf, F. A., P. Angerer and F. J. Theis (2018). "SCANPY: large-scale single-cell gene expression data analysis." Genome Biol 19(1): 15.Wolf, F. A., F. K. Hamey, M. Plass, J. Solana, J. S. Dahlin, B. Gottgens, N. Rajewsky, L. Simon and F. J. Theis (2019). "PAGA: graph abstraction reconciles clustering with trajectory inference through a topology preserving map of single cells." Genome Biol 20(1): 59.Wong, J., B. Johnston, S. S. Lee, D. C. Bullard, C. W. Smith, A. L. Beaudet and P. Kubes (1997). "A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature." J Clin Invest 99(11): 2782-2790.Wong, J. J., W. Ritchie, D. Gao, K. A. Lau, M. Gonzalez, A. Choudhary, R. J. Taft, J. E. Rasko and J. Holst (2014). "Identification of nuclear-enriched miRNAs during mouse granulopoiesis." J Hematol Oncol 7: 42.Wu, X., M. Zhao, B. Pan, J. Zhang, M. Peng, L. Wang, X. Hao, X. Huang, R. Mu, W. Guo, R. Qiao, W. Chen, H. Jiang, Y. Ma and H. Shang (2015). "Complete blood count reference intervals for healthy Han Chinese adults." PLoS One 10(3): e0119669.Wurm, A. A., P. Zjablovskaja, M. Kardosova, D. Gerloff, D. Brauer-Hartmann, C. Katzerke, J. U. Hartmann, T. Benoukraf, S. Fricke, N. Hilger, A. M. Muller, M. Bill, S. Schwind, D. G. Tenen, D. Niederwieser, M. Alberich-Jorda and G. Behre (2017). "Disruption of the C/EBPalpha-miR-182 balance impairs granulocytic differentiation." Nat Commun 8(1): 46.Xia, J., A. A. Bolyard, E. Rodger, S. Stein, A. A. Aprikyan, D. C. Dale and D. C. Link (2009). "Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia." Br J Haematol 147(4): 535-542.Xiao, C. and K. Rajewsky (2009). "MicroRNA control in the immune system: basic principles." Cell 136(1): 26-36.Xie, X., Q. Shi, P. Wu, X. Zhang, H. Kambara, J. Su, H. Yu, S. Y. Park, R. Guo, Q. Ren, S. Zhang, Y. Xu, L. E. Silberstein, T. Cheng, F. Ma, C. Li and H. R. Luo (2020). "Single-cell transcriptome profiling reveals neutrophil heterogeneity in homeostasis and infection." Nat Immunol 21(9): 1119-1133.Yamanaka, R., C. Barlow, J. Lekstrom-Himes, L. H. Castilla, P. P. Liu, M. Eckhaus, T. Decker, A. Wynshaw-Boris and K. G. Xanthopoulos (1997). "Impaired granulopoiesis, myelodysplasia, and early lethality in CCAAT/enhancer binding protein epsilon-deficient mice." Proc Natl Acad Sci U S A 94(24): 13187-13192.Yamanaka, R., G. D. Kim, H. S. Radomska, J. Lekstrom-Himes, L. T. Smith, P. Antonson, D. G. Tenen and K. G. Xanthopoulos (1997). "CCAAT/enhancer binding protein epsilon is preferentially up-regulated during granulocytic differentiation and its functional versatility is determined by alternative use of promoters and differential splicing." Proc Natl Acad Sci U S A 94(12): 6462-6467.Yates, A. D., P. Achuthan, W. Akanni, J. Allen, J. Allen, J. Alvarez-Jarreta, M. R. Amode, I. M. Armean, A. G. Azov, R. Bennett, J. Bhai, K. Billis, S. Boddu, J. C. Marugan, C. Cummins, C. Davidson, K. Dodiya, R. Fatima, A. Gall, C. G. Giron, L. Gil, T. Grego, L. Haggerty, E. Haskell, T. Hourlier, O. G. Izuogu, S. H. Janacek, T. Juettemann, M. Kay, I. Lavidas, T. Le, D. Lemos, J. G. Martinez, T. Maurel, M. McDowall, A. McMahon, S. Mohanan, B. Moore, M. Nuhn, D. N. Oheh, A. Parker, A. Parton, M. Patricio, M. P. Sakthivel, A. I. Abdul Salam, B. M. Schmitt, H. Schuilenburg, D. Sheppard, M. Sycheva, M. Szuba, K. Taylor, A. Thormann, G. Threadgold, A. Vullo, B. Walts, A. Winterbottom, A. Zadissa, M. Chakiachvili, B. Flint, A. Frankish, S. E. Hunt, I. I. G, M. Kostadima, N. Langridge, J. E. Loveland, F. J. Martin, J. Morales, J. M. Mudge, M. Muffato, E. Perry, M. Ruffier, S. J. Trevanion, F. Cunningham, K. L. Howe, D. R. Zerbino and P. Flicek (2020). "Ensembl 2020." Nucleic Acids Res 48(D1): D682-D688.Yipp, B. G., J. H. Kim, R. Lima, L. D. Zbytnuik, B. Petri, N. Swanlund, M. Ho, V. G. Szeto, T. Tak, L. Koenderman, P. Pickkers, A. T. J. Tool, T. W. Kuijpers, T. K. van den Berg, M. R. Looney, M. F. Krummel and P. Kubes (2017). "The Lung is a Host Defense Niche for Immediate Neutrophil-Mediated Vascular Protection." Sci Immunol 2(10).Zarbock, A., M. Allegretti and K. Ley (2008). "Therapeutic inhibition of CXCR2 by Reparixin attenuates acute lung injury in mice." Br J Pharmacol 155(3): 357-364.Zarbock, A., R. K. Polanowska-Grabowska and K. Ley (2007). "Platelet-neutrophil-interactions: linking hemostasis and inflammation." Blood Rev 21(2): 99-111.Zardo, G., A. Ciolfi, L. Vian, L. M. Starnes, M. Billi, S. Racanicchi, C. Maresca, F. Fazi, L. Travaglini, N. Noguera, M. Mancini, M. Nanni, G. Cimino, F. Lo-Coco, F. Grignani and C. Nervi (2012). "Polycombs and microRNA-223 regulate human granulopoiesis by transcriptional control of target gene expression." Blood 119(17): 4034-4046.Zhang, D. E., P. Zhang, N. D. Wang, C. J. Hetherington, G. J. Darlington and D. G. Tenen (1997). "Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice." Proc Natl Acad Sci U S A 94(2): 569-574.Zhang, L., R. Mack, P. Breslin and J. Zhang (2020). "Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches." J Hematol Oncol 13(1): 157.Zhang, P., J. Iwasaki-Arai, H. Iwasaki, M. L. Fenyus, T. Dayaram, B. M. Owens, H. Shigematsu, E. Levantini, C. S. Huettner, J. A. Lekstrom-Himes, K. Akashi and D. G. Tenen (2004). "Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha." Immunity 21(6): 853-863.Zhang, X. W., Q. Liu, Y. Wang and H. Thorlacius (2001). "CXC chemokines, MIP-2 and KC, induce P-selectin-dependent neutrophil rolling and extravascular migration in vivo." Br J Pharmacol 133(3): 413-421.Zhao, H., X. Wang, P. Yi, Y. Si, P. Tan, J. He, S. Yu, Y. Ren, Y. Ma, J. Zhang, D. Wang, F. Wang and J. Yu (2017). "KSRP specifies monocytic and granulocytic differentiation through regulating miR-129 biogenesis and RUNX1 expression." Nat Commun 8(1): 1428.Zheng, G. X., J. M. Terry, P. Belgrader, P. Ryvkin, Z. W. Bent, R. Wilson, S. B. Ziraldo, T. D. Wheeler, G. P. McDermott, J. Zhu, M. T. Gregory, J. Shuga, L. Montesclaros, J. G. Underwood, D. A. Masquelier, S. Y. Nishimura, M. Schnall-Levin, P. W. Wyatt, C. M. Hindson, R. Bharadwaj, A. Wong, K. D. Ness, L. W. Beppu, H. J. Deeg, C. McFarland, K. R. Loeb, W. J. Valente, N. G. Ericson, E. A. Stevens, J. P. Radich, T. S. Mikkelsen, B. J. Hindson and J. H. Bielas (2017). "Massively parallel digital transcriptional profiling of single cells." Nat Commun 8: 14049.Zhou, Y., B. Zhou, L. Pache, M. Chang, A. H. Khodabakhshi, O. Tanaseichuk, C. Benner and S. K. Chanda (2019). "Metascape provides a biologist-oriented resource for the analysis of systems-level datasets." Nat Commun 10(1): 1523.Zhu, Q. S., L. J. Robinson, V. Roginskaya and S. J. Corey (2004). "G-CSF-induced tyrosine phosphorylation of Gab2 is Lyn kinase dependent and associated with enhanced Akt and differentiative, not proliferative, responses." Blood 103(9): 3305-3312.Zhu, Q. S., L. Xia, G. B. Mills, C. A. Lowell, I. P. Touw and S. J. Corey (2006). "G-CSF induced reactive oxygen species involves Lyn-PI3-kinase-Akt and contributes to myeloid cell growth." Blood 107(5): 1847-1856.Zhu, Y. P., T. Eggert, D. J. Araujo, P. Vijayanand, C. H. Ottensmeier and C. C. Hedrick (2020). "CyTOF mass cytometry reveals phenotypically distinct human blood neutrophil populations differentially correlated with melanoma stage." J Immunother Cancer 8(2).Zhu, Y. P., L. Padgett, H. Q. Dinh, P. Marcovecchio, A. Blatchley, R. Wu, E. Ehinger, C. Kim, Z. Mikulski, G. Seumois, A. Madrigal, P. Vijayanand and C. C. Hedrick (2018). "Identification of an Early Unipotent Neutrophil Progenitor with Pro-tumoral Activity in Mouse and Human Bone Marrow." Cell Rep 24(9): 2329-2341 e2328.Zweidler-Mckay, P. A., H. L. Grimes, M. M. Flubacher and P. N. Tsichlis (1996). "Gfi-1 encodes a nuclear zinc finger protein that binds DNA and functions as a transcriptional repressor." Mol Cell Biol 16(8): 4024-4034.