Neutrophils: Between Host Defence, Immune Modulation, and Tissue Injury

1. Rørvig S, Østergaard O, Heegaard NHH, Borregaard N (2013) Proteome profiling of human neutrophil granule subsets, secretory vesicles, and cell membrane: correlation with transcriptome profiling of neutrophil precursors. Journal of Leukocyte Biology 94: 711–721. doi: 10.1189/jlb.1212619 23650620

2. Semerad CL, Liu F, Gregory AD, Stumpf K, Link DC (2002) G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity 17: 413–423. 12387736

3. Summers C, Rankin SM, Condliffe AM, Singh N, Peters AM, et al. (2010) Neutrophil kinetics in health and disease. Trends Immunol 31: 318–324. doi: 10.1016/j.it.2010.05.006 20620114

4. Lieschke GJ, Grail D, Hodgson G, Metcalf D, Stanley E, et al. (1994) Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 84: 1737–1746. 7521686

5. Basu S, Hodgson G, Katz M, Dunn AR (2002) Evaluation of role of G-CSF in the production, survival, and release of neutrophils from bone marrow into circulation. Blood 100: 854–861. 12130495

6. Hibbs ML, Quilici C, Kountouri N, Seymour JF, Armes JE, et al. (2007) Mice lacking three myeloid colony-stimulating factors (G-CSF, GM-CSF, and M-CSF) still produce macrophages and granulocytes and mount an inflammatory response in a sterile model of peritonitis. J Immunol 178: 6435–6443. 17475873

7. Christopher MJ, Link DC (2007) Regulation of neutrophil homeostasis. Curr Opin Hematol 14: 3–8. 17133093

8. Luo HR, Loison F (2008) Constitutive neutrophil apoptosis: mechanisms and regulation. Am J Hematol 83: 288–295. 17924549

9. Stark MA, Huo Y, Burcin TL, Morris MA, Olson TS, et al. (2005) Phagocytosis of Apoptotic Neutrophils Regulates Granulopoiesis via IL-23 and IL-17. Immunity 22: 285–294. 15780986

10. Rozman S, Yousefi S, Oberson K, Kaufmann T, Benarafa C, et al. (2014) The generation of neutrophils in the bone marrow is controlled by autophagy. Cell Death Differ.

11. Martin C, Burdon PC, Bridger G, Gutierrez-Ramos JC, Williams TJ, et al. (2003) Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 19: 583–593. 14563322

12. Holz O, Khalilieh S, Ludwig-Sengpiel A, Watz H, Stryszak P, et al. (2010) SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur Respir J 35: 564–570. doi: 10.1183/09031936.00048509 19643947

13. Lazaar AL, Sweeney LE, MacDonald AJ, Alexis NE, Chen C, et al. (2011) SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans. Br J Clin Pharmacol 72: 282–293. doi: 10.1111/j.1365-2125.2011.03968.x 21426372

14. Virtala R, Ekman AK, Jansson L, Westin U, Cardell LO (2012) Airway inflammation evaluated in a human nasal lipopolysaccharide challenge model by investigating the effect of a CXCR2 inhibitor. Clin Exp Allergy 42: 590–596. doi: 10.1111/j.1365-2222.2011.03921.x 22192144

15. Leaker BR, Barnes PJ, O'Connor B (2013) Inhibition of LPS-induced airway neutrophilic inflammation in healthy volunteers with an oral CXCR2 antagonist. Respir Res 14: 137. doi: 10.1186/1465-9921-14-137 24341382

16. Nair P, Gaga M, Zervas E, Alagha K, Hargreave FE, et al. (2012) Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy 42: 1097–1103. doi: 10.1111/j.1365-2222.2012.04014.x 22702508

17. Moss RB, Mistry SJ, Konstan MW, Pilewski JM, Kerem E, et al. (2013) Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis. J Cyst Fibros 12: 241–248. doi: 10.1016/j.jcf.2012.08.016 22995323

18. Vandivier RW, Henson PM, Douglas IS (2006) Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest 129: 1673–1682. 16778289

19. A-Gonzalez N, Bensinger SJ, Hong C, Beceiro S, Bradley MN, et al. (2009) Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31: 245–258. doi: 10.1016/j.immuni.2009.06.018 19646905

20. Hong C, Kidani Y, A-Gonzalez N, Phung T, Ito A, et al. (2012) Coordinate regulation of neutrophil homeostasis by liver X receptors in mice. J Clin Invest 122: 337–347. doi: 10.1172/JCI58393 22156197

21. Furze RC, Rankin SM (2008) The role of the bone marrow in neutrophil clearance under homeostatic conditions in the mouse. FASEB J 22: 3111–3119. doi: 10.1096/fj.08-109876 18509199

22. Casanova-Acebes M, Pitaval C, Weiss LA, Nombela-Arrieta C, Chevre R, et al. (2013) Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell 153: 1025–1035. doi: 10.1016/j.cell.2013.04.040 23706740

23. Buckley CD, Ross EA, McGettrick HM, Osborne CE, Haworth O, et al. (2006) Identification of a phenotypically and functionally distinct population of long-lived neutrophils in a model of reverse endothelial migration. J Leukoc Biol 79: 303–311. 16330528

24. Woodfin A, Voisin MB, Beyrau M, Colom B, Caille D, et al. (2011) The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo. Nat Immunol 12: 761–769. doi: 10.1038/ni.2062 21706006

25. Shelef MA, Tauzin S, Huttenlocher A (2013) Neutrophil migration: moving from zebrafish models to human autoimmunity. Immunol Rev 256: 269–281. doi: 10.1111/imr.12124 24117827

26. Athens JW, Haab OP, Raab SO, Mauer AM, Ashenbrucker H, et al. (1961) Leukokinetic studies. IV. The total blood, circulating and marginal granulocyte pools and the granulocyte turnover rate in normal subjects. J Clin Invest 40: 989–995. 13684958

27. Devi S, Wang Y, Chew WK, Lima R, A-González N, et al. (2013) Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow. The Journal of Experimental Medicine 210: 2321–2336. doi: 10.1084/jem.20130056 24081949

28. Summers C, Singh NR, White JF, Mackenzie IM, Johnston A, et al. (2014) Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome. Thorax 69: 623–629. doi: 10.1136/thoraxjnl-2013-204742 24706039

29. Pillay J, den Braber I, Vrisekoop N, Kwast LM, de Boer RJ, et al. (2010) In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood 116: 625–627. doi: 10.1182/blood-2010-01-259028 20410504

30. Tofts PS, Chevassut T, Cutajar M, Dowell NG, Peters AM (2011) Doubts concerning the recently reported human neutrophil lifespan of 5.4 days. Blood 117: 6050–6052; author reply 6053–6054. doi: 10.1182/blood-2010-10-310532 21636720

31. Li KW, Turner SM, Emson CL, Hellerstein MK, Dale DC (2011) Deuterium and neutrophil kinetics. Blood 117: 6052–6053; author reply 6053–6054. doi: 10.1182/blood-2010-12-322271 21636721

32. Pham CT (2006) Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol 6: 541–550. 16799473

33. Borregaard N (2010) Neutrophils, from marrow to microbes. Immunity 33: 657–670. doi: 10.1016/j.immuni.2010.11.011 21094463

34. Korkmaz B, Horwitz MS, Jenne DE, Gauthier F (2010) Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases. Pharmacol Rev 62: 726–759. doi: 10.1124/pr.110.002733 21079042

35. Benarafa C, LeCuyer TE, Baumann M, Stolley JM, Cremona TP, et al. (2011) SerpinB1 protects the mature neutrophil reserve in the bone marrow. J Leukoc Biol 90: 21–29. doi: 10.1189/jlb.0810461 21248149

36. Benarafa C, Priebe GP, Remold-O'Donnell E (2007) The neutrophil serine protease inhibitor serpinb1 preserves lung defense functions in Pseudomonas aeruginosa infection. J Exp Med 204: 1901–1909. 17664292

37. Gong D, Farley K, White M, Hartshorn KL, Benarafa C, et al. (2011) Critical role of serpinB1 in regulating inflammatory responses in pulmonary influenza infection. J Infect Dis 204: 592–600. doi: 10.1093/infdis/jir352 21791661

38. Baumann M, Pham CT, Benarafa C (2013) SerpinB1 is critical for neutrophil survival through cell-autonomous inhibition of cathepsin G. Blood 121: 3900–3907, S3901–3906. doi: 10.1182/blood-2012-09-455022 23532733

39. Loison F, Zhu H, Karatepe K, Kasorn A, Liu P, et al. (2014) Proteinase 3-dependent caspase-3 cleavage modulates neutrophil death and inflammation. J Clin Invest 124: 4445–4458. doi: 10.1172/JCI76246 25180606

40. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, et al. (2004) Neutrophil extracellular traps kill bacteria. Science 303: 1532–1535. 15001782

41. Mitroulis I, Kourtzelis I, Kambas K, Rafail S, Chrysanthopoulou A, et al. (2010) Regulation of the autophagic machinery in human neutrophils. Eur J Immunol 40: 1461–1472. doi: 10.1002/eji.200940025 20162553

42. Mihalache CC, Simon HU (2012) Autophagy regulation in macrophages and neutrophils. Exp Cell Res 318: 1187–1192. doi: 10.1016/j.yexcr.2011.12.021 22245582

43. Hakkim A, Furnrohr BG, Amann K, Laube B, Abed UA, et al. (2010) Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A 107: 9813–9818. doi: 10.1073/pnas.0909927107 20439745

44. Yipp BG, Petri B, Salina D, Jenne CN, Scott BN, et al. (2012) Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med 18: 1386–1393. 22922410

45. Harding MG, Zhang K, Conly J, Kubes P (2014) Neutrophil Crawling in Capillaries; A Novel Immune Response to Staphylococcus aureus. PLoS Pathog 10: e1004379. doi: 10.1371/journal.ppat.1004379 25299673

46. McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P (2012) Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 12: 324–333. doi: 10.1016/j.chom.2012.06.011 22980329

47. Jenne CN, Wong CH, Zemp FJ, McDonald B, Rahman MM, et al. (2013) Neutrophils recruited to sites of infection protect from virus challenge by releasing neutrophil extracellular traps. Cell Host Microbe 13: 169–180. doi: 10.1016/j.chom.2013.01.005 23414757

48. Rada BK, Geiszt M, Kaldi K, Timar C, Ligeti E (2004) Dual role of phagocytic NADPH oxidase in bacterial killing. Blood 104: 2947–2953. 15251984

49. Reeves EP, Lu H, Jacobs HL, Messina CGM, Bolsover S, et al. (2002) Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 416: 291–297. 11907569

50. Roos D, Winterbourn CC (2002) Immunology. Lethal weapons. Science 296: 669–671. 11976433

51. Sørensen OE, Clemmensen SN, Dahl SL, Ostergaard O, Heegaard NH, et al. (2014) Papillon-Lefevre syndrome patient reveals species-dependent requirements for neutrophil defenses. J Clin Invest 124: 4539–4548. doi: 10.1172/JCI76009 25244098

52. Gerber CE, Bruchelt G, Falk UB, Kimpfler A, Hauschild O, et al. (2001) Reconstitution of bactericidal activity in chronic granulomatous disease cells by glucose-oxidase-containing liposomes. Blood 98: 3097–3105. 11698296

53. Nakamura H, Fang J, Mizukami T, Nunoi H, Maeda H (2012) PEGylated d-amino acid oxidase restores bactericidal activity of neutrophils in chronic granulomatous disease via hypochlorite. Experimental Biology and Medicine 237: 703–708. doi: 10.1258/ebm.2012.011360 22715431

54. Standish AJ, Weiser JN (2009) Human neutrophils kill Streptococcus pneumoniae via serine proteases. J Immunol 183: 2602–2609. doi: 10.4049/jimmunol.0900688 19620298

55. Sokolovska A, Becker CE, Ip WK, Rathinam VA, Brudner M, et al. (2013) Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function. Nat Immunol 14: 543–553. doi: 10.1038/ni.2595 23644505

56. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, et al. (2007) Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 176: 231–241. 17210947

57. Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A (2010) Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol 191: 677–691. doi: 10.1083/jcb.201006052 20974816

58. Yousefi S, Mihalache C, Kozlowski E, Schmid I, Simon HU (2009) Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps. Cell Death Differ 16: 1438–1444. doi: 10.1038/cdd.2009.96 19609275

59. Bianchi M, Hakkim A, Brinkmann V, Siler U, Seger RA, et al. (2009) Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood 114: 2619–2622. doi: 10.1182/blood-2009-05-221606 19541821

60. Pilsczek FH, Salina D, Poon KK, Fahey C, Yipp BG, et al. (2010) A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J Immunol 185: 7413–7425. doi: 10.4049/jimmunol.1000675 21098229

61. Parker H, Dragunow M, Hampton MB, Kettle AJ, Winterbourn CC (2012) Requirements for NADPH oxidase and myeloperoxidase in neutrophil extracellular trap formation differ depending on the stimulus. Journal of Leukocyte Biology 92: 841–849. doi: 10.1189/jlb.1211601 22802447

62. Byrd AS, O'Brien XM, Johnson CM, Lavigne LM, Reichner JS (2013) An extracellular matrix-based mechanism of rapid neutrophil extracellular trap formation in response to Candida albicans. J Immunol 190: 4136–4148. doi: 10.4049/jimmunol.1202671 23509360

63. Arai Y, Nishinaka Y, Arai T, Morita M, Mizugishi K, et al. (2014) Uric acid induces NADPH oxidase-independent neutrophil extracellular trap formation. Biochem Biophys Res Commun 443: 556–561. doi: 10.1016/j.bbrc.2013.12.007 24326071

64. Wang Y, Li M, Stadler S, Correll S, Li P, et al. (2009) Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol 184: 205–213. doi: 10.1083/jcb.200806072 19153223

65. Hakkim A, Fuchs TA, Martinez NE, Hess S, Prinz H, et al. (2011) Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation. Nat Chem Biol 7: 75–77. doi: 10.1038/nchembio.496 21170021

66. Remijsen Q, Vanden Berghe T, Wirawan E, Asselbergh B, Parthoens E, et al. (2011) Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res 21: 290–304. doi: 10.1038/cr.2010.150 21060338

67. Sumby P, Barbian KD, Gardner DJ, Whitney AR, Welty DM, et al. (2005) Extracellular deoxyribonuclease made by group A Streptococcus assists pathogenesis by enhancing evasion of the innate immune response. Proc Natl Acad Sci U S A 102: 1679–1684. 15668390

68. Beiter K, Wartha F, Albiger B, Normark S, Zychlinsky A, et al. (2006) An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Curr Biol 16: 401–407. 16488875

69. Walker MJ, Hollands A, Sanderson-Smith ML, Cole JN, Kirk JK, et al. (2007) DNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection. Nat Med 13: 981–985. 17632528

70. Menegazzi R, Decleva E, Dri P (2012) Killing by neutrophil extracellular traps: fact or folklore? Blood 119: 1214–1216. doi: 10.1182/blood-2011-07-364604 22210873

71. Kessenbrock K, Krumbholz M, Schonermarck U, Back W, Gross WL, et al. (2009) Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 15: 623–625. doi: 10.1038/nm.1959 19448636

72. Thomas GM, Carbo C, Curtis BR, Martinod K, Mazo IB, et al. (2012) Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice. Blood 119: 6335–6343. doi: 10.1182/blood-2012-01-405183 22596262

73. Caudrillier A, Kessenbrock K, Gilliss BM, Nguyen JX, Marques MB, et al. (2012) Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest 122: 2661–2671. doi: 10.1172/JCI61303 22684106

74. Doring Y, Manthey HD, Drechsler M, Lievens D, Megens RT, et al. (2012) Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation 125: 1673–1683. doi: 10.1161/CIRCULATIONAHA.111.046755 22388324

75. Liu CL, Tangsombatvisit S, Rosenberg JM, Mandelbaum G, Gillespie EC, et al. (2012) Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies. Arthritis Res Ther 14: R25. doi: 10.1186/ar3707 22300536

76. Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, et al. (2013) NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med 5: 178ra140.

77. Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, et al. (2010) Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 16: 887–896. doi: 10.1038/nm.2184 20676107

78. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, et al. (2010) Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 107: 15880–15885. doi: 10.1073/pnas.1005743107 20798043

79. von Brühl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, et al. (2012) Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 209: 819–835. doi: 10.1084/jem.20112322 22451716

80. Martinod K, Demers M, Fuchs TA, Wong SL, Brill A, et al. (2013) Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc Natl Acad Sci U S A 110: 8674–8679. doi: 10.1073/pnas.1301059110 23650392

81. Schauer C, Janko C, Munoz LE, Zhao Y, Kienhofer D, et al. (2014) Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med 20: 511–517. doi: 10.1038/nm.3547 24784231

82. Villanueva E, Yalavarthi S, Berthier CC, Hodgin JB, Khandpur R, et al. (2011) Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol 187: 538–552. doi: 10.4049/jimmunol.1100450 21613614

83. Papayannopoulos V, Staab D, Zychlinsky A (2011) Neutrophil elastase enhances sputum solubilization in cystic fibrosis patients receiving DNase therapy. PLoS One 6: e28526. doi: 10.1371/journal.pone.0028526 22174830

84. Manzenreiter R, Kienberger F, Marcos V, Schilcher K, Krautgartner WD, et al. (2012) Ultrastructural characterization of cystic fibrosis sputum using atomic force and scanning electron microscopy. J Cyst Fibros 11: 84–92. doi: 10.1016/j.jcf.2011.09.008 21996135

85. Yipp BG, Kubes P (2013) NETosis: how vital is it? Blood 122: 2784–2794. doi: 10.1182/blood-2013-04-457671 24009232

86. Branzk N, Lubojemska A, Hardison SE, Wang Q, Gutierrez MG, et al. (2014) Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nat Immunol 15: 1017–1025. doi: 10.1038/ni.2987 25217981

87. Welin A, Amirbeagi F, Christenson K, Bjorkman L, Bjornsdottir H, et al. (2013) The human neutrophil subsets defined by the presence or absence of OLFM4 both transmigrate into tissue in vivo and give rise to distinct NETs in vitro. PLoS One 8: e69575. doi: 10.1371/journal.pone.0069575 23922742

88. Peschel A, Hartl D (2012) Anuclear neutrophils keep hunting. Nat Med 18: 1336–1338. doi: 10.1038/nm.2918 22961160

89. Peters BM, Shirtliff ME, Jabra-Rizk MA (2010) Antimicrobial peptides: primeval molecules or future drugs? PLoS Pathog 6: e1001067. doi: 10.1371/journal.ppat.1001067 21060861

90. Ohkubo T, Tsuda M, Tamura M, Yamamura M (1990) Impaired superoxide production in peripheral blood neutrophils of germ-free rats. Scand J Immunol 32: 727–729. 1702900

91. Deshmukh HS, Liu Y, Menkiti OR, Mei J, Dai N, et al. (2014) The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat Med 20: 524–530. doi: 10.1038/nm.3542 24747744

92. Kanther M, Tomkovich S, Xiaolun S, Grosser MR, Koo J, et al. (2014) Commensal microbiota stimulate systemic neutrophil migration through induction of serum amyloid A. Cell Microbiol 16: 1053–1067. doi: 10.1111/cmi.12257 24373309

93. Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, et al. (2010) Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med 16: 228–231. doi: 10.1038/nm.2087 20081863

94. Bugl S, Wirths S, Radsak MP, Schild H, Stein P, et al. (2013) Steady-state neutrophil homeostasis is dependent on TLR4/TRIF signaling. Blood 121: 723–733. doi: 10.1182/blood-2012-05-429589 23223360

95. Balmer ML, Schurch CM, Saito Y, Geuking MB, Li H, et al. (2014) Microbiota-Derived Compounds Drive Steady-State Granulopoiesis via MyD88/TICAM Signaling. J Immunol 193: 5273–5283. doi: 10.4049/jimmunol.1400762 25305320

96. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, et al. (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461: 1282–1286. doi: 10.1038/nature08530 19865172

97. Schwabe RF, Jobin C (2013) The microbiome and cancer. Nat Rev Cancer 13: 800–812. doi: 10.1038/nrc3610 24132111

98. Gargano LM, Hughes JM (2014) Microbial origins of chronic diseases. Annu Rev Public Health 35: 65–82. doi: 10.1146/annurev-publhealth-032013-182426 24365095

99. Mocsai A (2013) Diverse novel functions of neutrophils in immunity, inflammation, and beyond. J Exp Med 210: 1283–1299. doi: 10.1084/jem.20122220 23825232

100. Scapini P, Cassatella MA (2014) Social networking of human neutrophils within the immune system. Blood 124: 710–719. doi: 10.1182/blood-2014-03-453217 24923297

101. Peters NC, Kimblin N, Secundino N, Kamhawi S, Lawyer P, et al. (2009) Vector transmission of leishmania abrogates vaccine-induced protective immunity. PLoS Pathog 5: e1000484. doi: 10.1371/journal.ppat.1000484 19543375

102. Ribeiro-Gomes FL, Peters NC, Debrabant A, Sacks DL (2012) Efficient capture of infected neutrophils by dendritic cells in the skin inhibits the early anti-leishmania response. PLoS Pathog 8: e1002536. doi: 10.1371/journal.ppat.1002536 22359507

103. Pelletier M, Maggi L, Micheletti A, Lazzeri E, Tamassia N, et al. (2010) Evidence for a cross-talk between human neutrophils and Th17 cells. Blood 115: 335–343. doi: 10.1182/blood-2009-04-216085 19890092

104. Scapini P, Carletto A, Nardelli B, Calzetti F, Roschke V, et al. (2005) Proinflammatory mediators elicit secretion of the intracellular B-lymphocyte stimulator pool (BLyS) that is stored in activated neutrophils: implications for inflammatory diseases. Blood 105: 830–837. 15358625

105. Huard B, McKee T, Bosshard C, Durual S, Matthes T, et al. (2008) APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa. J Clin Invest 118: 2887–2895. doi: 10.1172/JCI33760 18618015

106. Rauch PJ, Chudnovskiy A, Robbins CS, Weber GF, Etzrodt M, et al. (2012) Innate response activator B cells protect against microbial sepsis. Science 335: 597–601. doi: 10.1126/science.1215173 22245738

107. Cerutti A, Puga I, Magri G (2013) The B cell helper side of neutrophils. J Leukoc Biol 94: 677–682. doi: 10.1189/jlb.1112596 23630389

108. Puga I, Cols M, Barra CM, He B, Cassis L, et al. (2012) B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol 13: 170–180. doi: 10.1038/ni.2194 22197976

109. Nagelkerke SQ, aan de Kerk DJ, Jansen MH, van den Berg TK, Kuijpers TW (2014) Failure to detect functional neutrophil B helper cells in the human spleen. PLoS One 9: e88377. doi: 10.1371/journal.pone.0088377 24523887

110. Youn JI, Gabrilovich DI (2010) The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol 40: 2969–2975. doi: 10.1002/eji.201040895 21061430

111. Munder M, Mollinedo F, Calafat J, Canchado J, Gil-Lamaignere C, et al. (2005) Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood 105: 2549–2556. 15546957

112. Kraaij MD, Savage ND, van der Kooij SW, Koekkoek K, Wang J, et al. (2010) Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species. Proc Natl Acad Sci U S A 107: 17686–17691. doi: 10.1073/pnas.1012016107 20861446

113. Nagaraj S, Youn JI, Gabrilovich DI (2013) Reciprocal relationship between myeloid-derived suppressor cells and T cells. J Immunol 191: 17–23. doi: 10.4049/jimmunol.1300654 23794702

114. Pillay J, Kamp VM, van Hoffen E, Visser T, Tak T, et al. (2012) A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1. J Clin Invest 122: 327–336. doi: 10.1172/JCI57990 22156198

115. Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, et al. (2000) Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 96: 2317–2322. 11001877

116. Köllner I, Sodeik B, Schreek S, Heyn H, von Neuhoff N, et al. (2006) Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response. Blood 108: 493–500. 16551967

117. Grenda DS, Murakami M, Ghatak J, Xia J, Boxer LA, et al. (2007) Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Blood 110: 4179–4187. 17761833

118. Carlsson G, Aprikyan AA, Tehranchi R, Dale DC, Porwit A, et al. (2004) Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells. Blood 103: 3355–3361. 14764541

119. Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, et al. (2007) HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet 39: 86–92. 17187068

120. Skokowa J, Cario G, Uenalan M, Schambach A, Germeshausen M, et al. (2006) LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nat Med 12: 1191–1197. 17063141

121. Skokowa J, Klimiankou M, Klimenkova O, Lan D, Gupta K, et al. (2012) Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis. Nat Med 18: 1550–1559. doi: 10.1038/nm.2958 23001182

122. Person RE, Li FQ, Duan ZJ, Benson KF, Wechsler J, et al. (2003) Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nature Genetics 34: 308–312. 12778173

123. Devriendt K, Kim AS, Mathijs G, Frints SG, Schwartz M, et al. (2001) Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet 27: 313–317. 11242115

124. Boztug K, Appaswamy G, Ashikov A, Schaffer AA, Salzer U, et al. (2009) A syndrome with congenital neutropenia and mutations in G6PC3. N Engl J Med 360: 32–43. doi: 10.1056/NEJMoa0805051 19118303

125. Bohn G, Allroth A, Brandes G, Thiel J, Glocker E, et al. (2007) A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nat Med 13: 38–45. 17195838

126. Vilboux T, Lev A, Malicdan MC, Simon AJ, Jarvinen P, et al. (2013) A congenital neutrophil defect syndrome associated with mutations in VPS45. N Engl J Med 369: 54–65. doi: 10.1056/NEJMoa1301296 23738510

127. Winkelstein JA, Marino MC, Johnston RB Jr., Boyle J, Curnutte J, et al. (2000) Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 79: 155–169. 10844935

128. van den Berg JM, van Koppen E, Ahlin A, Belohradsky BH, Bernatowska E, et al. (2009) Chronic granulomatous disease: the European experience. PLoS One 4: e5234. doi: 10.1371/journal.pone.0005234 19381301

129. Köker MY, Camcioglu Y, van Leeuwen K, Kilic SS, Barlan I, et al. (2013) Clinical, functional, and genetic characterization of chronic granulomatous disease in 89 Turkish patients. J Allergy Clin Immunol.

130. Roos D, Kuhns DB, Maddalena A, Bustamante J, Kannengiesser C, et al. (2010) Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (second update). Blood Cells Mol Dis 44: 291–299. doi: 10.1016/j.bcmd.2010.01.009 20167518

131. Roos D, Kuhns DB, Maddalena A, Roesler J, Lopez JA, et al. (2010) Hematologically important mutations: X-linked chronic granulomatous disease (third update). Blood Cells Mol Dis 45: 246–265. doi: 10.1016/j.bcmd.2010.07.012 20729109

132. Anderson-Cohen M, Holland SM, Kuhns DB, Fleisher TA, Ding L, et al. (2003) Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial, extremely skewed X chromosome inactivation. Clin Immunol 109: 308–317. 14697745

133. de Luca A, Smeekens SP, Casagrande A, Iannitti R, Conway KL, et al. (2014) IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans. Proc Natl Acad Sci U S A 111: 3526–3531. doi: 10.1073/pnas.1322831111 24550444

134. Segal BH, Han W, Bushey JJ, Joo M, Bhatti Z, et al. (2010) NADPH oxidase limits innate immune responses in the lungs in mice. PLoS One 5: e9631. doi: 10.1371/journal.pone.0009631 20300512

135. Marciano BE, Rosenzweig SD, Kleiner DE, Anderson VL, Darnell DN, et al. (2004) Gastrointestinal involvement in chronic granulomatous disease. Pediatrics 114: 462–468. 15286231

136. Jones LB, McGrogan P, Flood TJ, Gennery AR, Morton L, et al. (2008) Special article: chronic granulomatous disease in the United Kingdom and Ireland: a comprehensive national patient-based registry. Clin Exp Immunol 152: 211–218. doi: 10.1111/j.1365-2249.2008.03644.x 18410635

137. Campbell EL, Bruyninckx WJ, Kelly CJ, Glover LE, McNamee EN, et al. (2014) Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity 40: 66–77. doi: 10.1016/j.immuni.2013.11.020 24412613

138. Harris ES, Weyrich AS, Zimmerman GA (2013) Lessons from rare maladies: leukocyte adhesion deficiency syndromes. Curr Opin Hematol 20: 16–25. doi: 10.1097/MOH.0b013e32835a0091 23207660

139. Sanchez-Madrid F, Nagy JA, Robbins E, Simon P, Springer TA (1983) A human leukocyte differentiation antigen family with distinct alpha-subunits and a common beta-subunit: the lymphocyte function-associated antigen (LFA-1), the C3bi complement receptor (OKM1/Mac-1), and the p150,95 molecule. J Exp Med 158: 1785–1803. 6196430

140. Anderson DC, Schmalstieg FC, Arnaout MA, Kohl S, Tosi MF, et al. (1984) Abnormalities of polymorphonuclear leukocyte function associated with a heritable deficiency of high molecular weight surface glycoproteins (GP138): common relationship to diminished cell adherence. J Clin Invest 74: 536–551. 6746906

141. Springer TA, Thompson WS, Miller LJ, Schmalstieg FC, Anderson DC (1984) Inherited deficiency of the Mac-1, LFA-1, p150,95 glycoprotein family and its molecular basis. J Exp Med 160: 1901–1918. 6096477

142. Roos D, Meischl C, de Boer M, Simsek S, Weening RS, et al. (2002) Genetic analysis of patients with leukocyte adhesion deficiency: genomic sequencing reveals otherwise undetectable mutations. Exp Hematol 30: 252–261. 11882363

143. van de Vijver E, Maddalena A, Sanal O, Holland SM, Uzel G, et al. (2012) Hematologically important mutations: leukocyte adhesion deficiency (first update). Blood Cells Mol Dis 48: 53–61. doi: 10.1016/j.bcmd.2011.10.004 22134107

144. Mathew EC, Shaw JM, Bonilla FA, Law SK, Wright DA (2000) A novel point mutation in CD18 causing the expression of dysfunctional CD11/CD18 leucocyte integrins in a patient with leucocyte adhesion deficiency (LAD). Clin Exp Immunol 121: 133–138. 10886250

145. Etzioni A, Frydman M, Pollack S, Avidor I, Phillips ML, et al. (1992) Brief report: recurrent severe infections caused by a novel leukocyte adhesion deficiency. N Engl J Med 327: 1789–1792. 1279426

146. Lühn K, Wild MK, Eckhardt M, Gerardy-Schahn R, Vestweber D (2001) The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter. Nat Genet 28: 69–72. 11326279

147. Lubke T, Marquardt T, Etzioni A, Hartmann E, von Figura K, et al. (2001) Complementation cloning identifies CDG-IIc, a new type of congenital disorders of glycosylation, as a GDP-fucose transporter deficiency. Nat Genet 28: 73–76. 11326280

148. Helmus Y, Denecke J, Yakubenia S, Robinson P, Luhn K, et al. (2006) Leukocyte adhesion deficiency II patients with a dual defect of the GDP-fucose transporter. Blood 107: 3959–3966. 16455955

149. Etzioni A, Sturla L, Antonellis A, Green ED, Gershoni-Baruch R, et al. (2002) Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein (CDG) IIc founder effect and genotype/phenotype correlation. Am J Med Genet 110: 131–135. 12116250

150. Kuijpers TW, Van Lier RA, Hamann D, de Boer M, Thung LY, et al. (1997) Leukocyte adhesion deficiency type 1 (LAD-1)/variant. A novel immunodeficiency syndrome characterized by dysfunctional beta2 integrins. J Clin Invest 100: 1725–1733. 9312170

151. Kuijpers TW, van Bruggen R, Kamerbeek N, Tool AT, Hicsonmez G, et al. (2007) Natural history and early diagnosis of LAD-1/variant syndrome. Blood 109: 3529–3537. 17185466

152. Kuijpers TW, van de Vijver E, Weterman MA, de Boer M, Tool AT, et al. (2009) LAD-1/variant syndrome is caused by mutations in FERMT3. Blood 113: 4740–4746. doi: 10.1182/blood-2008-10-182154 19064721

153. Harris ES, Smith TL, Springett GM, Weyrich AS, Zimmerman GA (2012) Leukocyte adhesion deficiency-I variant syndrome (LAD-Iv, LAD-III): molecular characterization of the defect in an index family. Am J Hematol 87: 311–313. doi: 10.1002/ajh.22253 22139635

154. van de Vijver E, De Cuyper IM, Gerrits AJ, Verhoeven AJ, Seeger K, et al. (2012) Defects in Glanzmann thrombasthenia and LAD-III (LAD-1/v) syndrome: the role of integrin beta1 and beta3 in platelet adhesion to collagen. Blood 119: 583–586. doi: 10.1182/blood-2011-02-337188 22065596

155. Ambruso DR, Knall C, Abell AN, Panepinto J, Kurkchubasche A, et al. (2000) Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc Natl Acad Sci U S A 97: 4654–4659. 10758162

156. Accetta D, Syverson G, Bonacci B, Reddy S, Bengtson C, et al. (2011) Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-cell lymphopenia. Journal of Allergy and Clinical Immunology 127: 535–538.e532. doi: 10.1016/j.jaci.2010.10.013 21167572

157. Moutsopoulos NM, Konkel J, Sarmadi M, Eskan MA, Wild T, et al. (2014) Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss. Sci Transl Med 6: 229ra240.

158. Gulino AV, Moratto D, Sozzani S, Cavadini P, Otero K, et al. (2004) Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome. Blood 104: 444–452. 15026312

159. Hayashi F, Means TK, Luster AD (2003) Toll-like receptors stimulate human neutrophil function. Blood 102: 2660–2669. 12829592

160. Bouma G, Doffinger R, Patel SY, Peskett E, Sinclair JC, et al. (2009) Impaired neutrophil migration and phagocytosis in IRAK-4 deficiency. Br J Haematol 147: 153–156. doi: 10.1111/j.1365-2141.2009.07838.x 19663824

161. van Bruggen R, Drewniak A, Tool AT, Jansen M, van Houdt M, et al. (2010) Toll-like receptor responses in IRAK-4-deficient neutrophils. J Innate Immun 2: 280–287. doi: 10.1159/000268288 20375545

162. Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, et al. (2003) Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299: 2076–2079. 12637671

163. Enders A, Pannicke U, Berner R, Henneke P, Radlinger K, et al. (2004) Two siblings with lethal pneumococcal meningitis in a family with a mutation in Interleukin-1 receptor-associated kinase 4. J Pediatr 145: 698–700. 15520784

164. von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, et al. (2008) Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321: 691–696. doi: 10.1126/science.1158298 18669862

165. Picard C, von Bernuth H, Ghandil P, Chrabieh M, Levy O, et al. (2010) Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore) 89: 403–425.

166. Picard C, Casanova JL, Puel A (2011) Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IkappaBalpha deficiency. Clin Microbiol Rev 24: 490–497. doi: 10.1128/CMR.00001-11 21734245

167. Glocker EO, Hennigs A, Nabavi M, Schaffer AA, Woellner C, et al. (2009) A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med 361: 1727–1735. doi: 10.1056/NEJMoa0810719 19864672

168. Drewniak A, Gazendam RP, Tool AT, van Houdt M, Jansen MH, et al. (2013) Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood 121: 2385–2392. doi: 10.1182/blood-2012-08-450551 23335372

169. Gombart AF, Shiohara M, Kwok SH, Agematsu K, Komiyama A, et al. (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: 2561–2567. 11313242

170. Klebanoff SJ, Kettle AJ, Rosen H, Winterbourn CC, Nauseef WM (2013) Myeloperoxidase: a front-line defender against phagocytosed microorganisms. J Leukoc Biol 93: 185–198. doi: 10.1189/jlb.0712349 23066164

171. Moraes TJ, Zurawska JH, Downey GP (2006) Neutrophil granule contents in the pathogenesis of lung injury. Curr Opin Hematol 13: 21–27. 16319683

172. Grommes J, Soehnlein O (2011) Contribution of neutrophils to acute lung injury. Mol Med 17: 293–307. doi: 10.2119/molmed.2010.00138 21046059

173. Kolaczkowska E, Kubes P (2013) Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 13: 159–175. doi: 10.1038/nri3399 23435331

174. Williams AE, Chambers RC (2014) The mercurial nature of neutrophils: still an enigma in ARDS? Am J Physiol Lung Cell Mol Physiol 306: L217–230. doi: 10.1152/ajplung.00311.2013 24318116

175. McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, et al. (2010) Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330: 362–366. doi: 10.1126/science.1195491 20947763

176. Serhan CN (2014) Pro-resolving lipid mediators are leads for resolution physiology. Nature 510: 92–101. doi: 10.1038/nature13479 24899309

177. Condliffe AM, Kitchen E, Chilvers ER (1998) Neutrophil priming: pathophysiological consequences and underlying mechanisms. Clin Sci (Lond) 94: 461–471. 9682667

178. Summers C, Chilvers ER, Peters AM (2014) Mathematical modeling supports the presence of neutrophil depriming in vivo. Physiol Rep 2: e00241. doi: 10.1002/phy2.241 24760504

179. Singh A, Zarember KA, Kuhns DB, Gallin JI (2009) Impaired priming and activation of the neutrophil NADPH oxidase in patients with IRAK4 or NEMO deficiency. J Immunol 182: 6410–6417. doi: 10.4049/jimmunol.0802512 19414794

180. McMillan SJ, Sharma RS, McKenzie EJ, Richards HE, Zhang J, et al. (2013) Siglec-E is a negative regulator of acute pulmonary neutrophil inflammation and suppresses CD11b beta2-integrin-dependent signaling. Blood 121: 2084–2094. doi: 10.1182/blood-2012-08-449983 23315163

181. Davidson BA, Vethanayagam RR, Grimm MJ, Mullan BA, Raghavendran K, et al. (2013) NADPH oxidase and Nrf2 regulate gastric aspiration-induced inflammation and acute lung injury. J Immunol 190: 1714–1724. doi: 10.4049/jimmunol.1202410 23296708

182. Schmidt EP, Yang Y, Janssen WJ, Gandjeva A, Perez MJ, et al. (2012) The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med 18: 1217–1223. doi: 10.1038/nm.2843 22820644

183. Achouiti A, Vogl T, Urban CF, Rohm M, Hommes TJ, et al. (2012) Myeloid-related protein-14 contributes to protective immunity in gram-negative pneumonia derived sepsis. PLoS Pathog 8: e1002987. doi: 10.1371/journal.ppat.1002987 23133376

184. Weckbach LT, Gola A, Winkelmann M, Jakob SM, Groesser L, et al. (2014) The cytokine midkine supports neutrophil trafficking during acute inflammation by promoting adhesion via beta2 integrins (CD11/CD18). Blood 123: 1887–1896. doi: 10.1182/blood-2013-06-510875 24458438

185. Jakob SM, Pick R, Brechtefeld D, Nussbaum C, Kiefer F, et al. (2013) Hematopoietic progenitor kinase 1 (HPK1) is required for LFA-1-mediated neutrophil recruitment during the acute inflammatory response. Blood 121: 4184–4194. doi: 10.1182/blood-2012-08-451385 23460610

186. Sutherland TE, Logan N, Ruckerl D, Humbles AA, Allan SM, et al. (2014) Chitinase-like proteins promote IL-17-mediated neutrophilia in a tradeoff between nematode killing and host damage. Nat Immunol.

187. Christoffersson G, Vagesjo E, Vandooren J, Liden M, Massena S, et al. (2012) VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue. Blood 120: 4653–4662. doi: 10.1182/blood-2012-04-421040 22966168

188. Weathington NM, van Houwelingen AH, Noerager BD, Jackson PL, Kraneveld AD, et al. (2006) A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation. Nat Med 12: 317–323. 16474398

189. Snelgrove RJ, Jackson PL, Hardison MT, Noerager BD, Kinloch A, et al. (2010) A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science 330: 90–94. doi: 10.1126/science.1190594 20813919

190. Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418: 191–195. 12110890

191. Schiraldi M, Raucci A, Munoz LM, Livoti E, Celona B, et al. (2012) HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4. J Exp Med 209: 551–563. doi: 10.1084/jem.20111739 22370717

192. Brandau S, Dumitru CA, Lang S (2013) Protumor and antitumor functions of neutrophil granulocytes. Semin Immunopathol 35: 163–176. doi: 10.1007/s00281-012-0344-6 23007469

193. Bauer S, Abdgawad M, Gunnarsson L, Segelmark M, Tapper H, et al. (2007) Proteinase 3 and CD177 are expressed on the plasma membrane of the same subset of neutrophils. J Leukoc Biol 81: 458–464. 17077162

194. Hartl D, Krauss-Etschmann S, Koller B, Hordijk PL, Kuijpers TW, et al. (2008) Infiltrated neutrophils acquire novel chemokine receptor expression and chemokine responsiveness in chronic inflammatory lung diseases. J Immunol 181: 8053–8067. 19017998

195. Tirouvanziam R, Gernez Y, Conrad CK, Moss RB, Schrijver I, et al. (2008) Profound functional and signaling changes in viable inflammatory neutrophils homing to cystic fibrosis airways. Proc Natl Acad Sci U S A 105: 4335–4339. doi: 10.1073/pnas.0712386105 18334635

196. Sigua JA, Buelow B, Cheung DS, Buell E, Hunter D, et al. (2014) CD49d-expressing neutrophils differentiate atopic from nonatopic individuals. J Allergy Clin Immunol 133: 901–904 e905. doi: 10.1016/j.jaci.2013.09.035 24360325

197. Puellmann K, Kaminski WE, Vogel M, Nebe CT, Schroeder J, et al. (2006) A variable immunoreceptor in a subpopulation of human neutrophils. Proc Natl Acad Sci U S A 103: 14441–14446. 16983085

198. Beyrau M, Bodkin JV, Nourshargh S (2012) Neutrophil heterogeneity in health and disease: a revitalized avenue in inflammation and immunity. Open Biol 2: 120134. doi: 10.1098/rsob.120134 23226600

199. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, et al. (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell 16: 183–194. doi: 10.1016/j.ccr.2009.06.017 19732719

200. Tsuda Y, Takahashi H, Kobayashi M, Hanafusa T, Herndon DN, et al. (2004) Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus. Immunity 21: 215–226. 15308102

201. Matsushima H, Geng S, Lu R, Okamoto T, Yao Y, et al. (2013) Neutrophil differentiation into a unique hybrid population exhibiting dual phenotype and functionality of neutrophils and dendritic cells. Blood 121: 1677–1689. doi: 10.1182/blood-2012-07-445189 23305731

202. Geng S, Matsushima H, Okamoto T, Yao Y, Lu R, et al. (2013) Emergence, origin, and function of neutrophil-dendritic cell hybrids in experimentally induced inflammatory lesions in mice. Blood 121: 1690–1700. doi: 10.1182/blood-2012-07-445197 23305733

203. Iking-Konert C, Ostendorf B, Sander O, Jost M, Wagner C, et al. (2005) Transdifferentiation of polymorphonuclear neutrophils to dendritic-like cells at the site of inflammation in rheumatoid arthritis: evidence for activation by T cells. Annals of the Rheumatic Diseases 64: 1436–1442. 15778239

204. Radsak M, Iking-Konert C, Stegmaier S, Andrassy K, Hänsch GM (2000) Polymorphonuclear neutrophils as accessory cells for T-cell activation: major histocompatibility complex class II restricted antigen-dependent induction of T-cell proliferation. Immunology 101: 521–530. 11122456

205. Pliyev BK, Sumarokov AB, Buriachkovskaia LI, Menshikov M (2011) Extracellular acidosis promotes neutrophil transdifferentiation to MHC class II-expressing cells. Cell Immunol 271: 214–218. doi: 10.1016/j.cellimm.2011.08.020 21924707

206. Dyugovskaya L, Berger S, Polyakov A, Lavie L (2014) The development of giant phagocytes in long-term neutrophil cultures. J Leukoc Biol 96: 511–521. doi: 10.1189/jlb.0813437 24577569

207. Köffel R, Meshcheryakova A, Warszawska J, Hennig A, Wagner K, et al. (2014) Monocytic cell differentiation from band-stage neutrophils under inflammatory conditions via MKK6 activation. Blood 124: 2713–2724. doi: 10.1182/blood-2014-07-588178 25214442

208. Makam M, Diaz D, Laval J, Gernez Y, Conrad CK, et al. (2009) Activation of critical, host-induced, metabolic and stress pathways marks neutrophil entry into cystic fibrosis lungs. Proc Natl Acad Sci U S A 106: 5779–5783. doi: 10.1073/pnas.0813410106 19293384

209. Laval J, Touhami J, Herzenberg LA, Conrad C, Taylor N, et al. (2013) Metabolic adaptation of neutrophils in cystic fibrosis airways involves distinct shifts in nutrient transporter expression. J Immunol 190: 6043–6050. doi: 10.4049/jimmunol.1201755 23690474

210. Youn JI, Kumar V, Collazo M, Nefedova Y, Condamine T, et al. (2013) Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat Immunol 14: 211–220. doi: 10.1038/ni.2526 23354483

211. Moss RB, Mistry SJ, Konstan MW, Pilewski JM, Kerem E, et al. (2013) Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis. J Cyst Fibros 12: 241–248. doi: 10.1016/j.jcf.2012.08.016 22995323