Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 145 No. 0708 (2015)

Promoting apoptosis of neutrophils and phagocytosis by macrophages: novel strategies in the resolution of inflammation

  • Katherine R Martin
  • Delphine Ohayon
  • Veronique Witko-Sarsat
Cite this as:
Swiss Med Wkly. 2015;145:w14056


Acute inflammation is the body’s response to infection or injury, characterised by the rapid infiltration of polymorphonuclear neutrophils to the site of injury followed by monocytes, which differentiate locally into macrophages. The latter are essential for the removal of effete neutrophils and provided that the harmful agent is eliminated, removal of neutrophils will lead to the resolution of inflammation. Perturbations in this process result in the persistence of inflammation and close control of pathways associated with resolution are necessary to avoid chronic inflammation, autoimmunity, or both. As our understanding of these processes increase, drugs able to trigger pro-resolution pathways may represent an effective strategy for treating chronic inflammatory diseases.


  1. Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005;6(12):1191–7.
  2. Kennedy AD, DeLeo FR. Neutrophil apoptosis and the resolution of infection. Immunol Res. 2009;43(1–3):25–61.
  3. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159–75.
  4. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell. 2009;16(3):183–94.
  5. Scapini P, Cassatella MA. Social networking of human neutrophils within the immune system. Blood. 2014;
  6. Nauseef WM, Borregaard N. Neutrophils at work. Nat Immunol. 2014;15(7):602–11.
  7. Cassatella MA, Locati M, Mantovani A. Never underestimate the power of a neutrophil. Immunity. 2009;31(5):698–700.
  8. Grotendorst GR, Smale G, Pencev D. Production of transforming growth factor beta by human peripheral blood monocytes and neutrophils. J Cell Physiol. 1989;140(2):396–402.
  9. Schroder AK, von der Ohe M, Kolling U, Altstaedt J, Uciechowski P, Fleischer D, et al. Polymorphonuclear leucocytes selectively produce anti-inflammatory interleukin-1 receptor antagonist and chemokines, but fail to produce pro-inflammatory mediators. Immunology. 2006;119(3):317–27.
  10. Zhang X, Majlessi L, Deriaud E, Leclerc C, Lo-Man R. Coactivation of Syk kinase and MyD88 adaptor protein pathways by bacteria promotes regulatory properties of neutrophils. Immunity. 2009;31(5):761–71.
  11. Fournier BM, Parkos CA. The role of neutrophils during intestinal inflammation. Mucosal Immunol. 2012;5(4):354–66.
  12. Rane MJ, Klein JB. Regulation of neutrophil apoptosis by modulation of PKB/Akt activation. Front Biosci (Landmark Ed). 2009;14:2400–12.
  13. Rossi AG, Sawatzky DA, Walker A, Ward C, Sheldrake TA, Riley NA, et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat Med. 2006;12(9):1056–64.
  14. Simon HU. Targeting apoptosis in the control of inflammation. Eur Respir J Suppl. 2003;44:20s–21s.
  15. Simon HU. Neutrophil apoptosis pathways and their modifications in inflammation. Immunol Rev. 2003;193:101–10.
  16. Fecho K, Cohen PL. Fas ligand (gld)- and Fas (lpr)-deficient mice do not show alterations in the extravasation or apoptosis of inflammatory neutrophils. J Leukoc Biol. 1998;64(3):373–83.
  17. Fox S, Leitch AE, Duffin R, Haslett C, Rossi AG. Neutrophil apoptosis: relevance to the innate immune response and inflammatory disease. J Innate Immun. 2010;2(3):216–27.
  18. Witko-Sarsat V, Pederzoli-Ribeil M, Hirsch E, Sozzani S, Cassatella MA. Regulating neutrophil apoptosis: new players enter the game. Trends Immunol. 2011;32(3):117–24.
  19. Blomgran R, Zheng L, Stendahl O. Cathepsin-cleaved Bid promotes apoptosis in human neutrophils via oxidative stress-induced lysosomal membrane permeabilization. J Leukoc Biol. 2007;81(5):1213–23.
  20. Moriceau S, Kantari C, Mocek J, Davezac N, Gabillet J, Guerrera IC, et al. Coronin-1 is associated with neutrophil survival and is cleaved during apoptosis: potential implication in neutrophils from cystic fibrosis patients. J Immunol. 2009;182(11):7254–63.
  21. Kaminski S, Hermann-Kleiter N, Meisel M, Thuille N, Cronin S, Hara H, et al. Coronin 1A is an essential regulator of the TGFbeta receptor/SMAD3 signaling pathway in Th17 CD4(+) T cells. J Autoimmun. 2011;37(3):198–208.
  22. Shiow LR, Roadcap DW, Paris K, Watson SR, Grigorova IL, Lebet T, et al. The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency. Nat Immunol. 2008;9(11):1307–15.
  23. Geering B, Stoeckle C, Conus S, Simon HU. Living and dying for inflammation: neutrophils, eosinophils, basophils. Trends Immunol. 2013;34(8):398–409.
  24. Nathan C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol. 2006;6(3):173–82.
  25. Thompson AA, Elks PM, Marriott HM, Eamsamarng S, Higgins KR, Lewis A, et al. Hypoxia-inducible factor 2alpha regulates key neutrophil functions in humans, mice, and zebrafish. Blood. 2014;123(3):366–76.
  26. Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, et al. Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med. 2005;201(1):105–15.
  27. Dzhagalov I, St John A, He YW. The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages. Blood. 2007;109(4):1620–6.
  28. Thomas LW, Lam C, Edwards SW. Mcl-1; the molecular regulation of protein function. FEBS Lett. 2010;584(14):2981–9.
  29. Altznauer F, Martinelli S, Yousefi S, Thurig C, Schmid I, Conway EM, et al. Inflammation-associated cell cycle-independent block of apoptosis by survivin in terminally differentiated neutrophils. J Exp Med. 2004;199(10):1343–54.
  30. Moldovan GL, Pfander B, Jentsch S. PCNA, the maestro of the replication fork. Cell. 2007;129(4):665–79.
  31. Warbrick E. The puzzle of PCNA's many partners. Bioessays. 2000;22(11):997–1006.
  32. Maga G, Hubscher U. Proliferating cell nuclear antigen (PCNA): a dancer with many partners. J Cell Sci. 2003;116(Pt 15):3051–60.
  33. Sugiyama M, Tsukazaki T, Yonekura A, Matsuzaki S, Yamashita S, Iwasaki K. Localisation of apoptosis and expression of apoptosis related proteins in the synovium of patients with rheumatoid arthritis. Ann Rheum Dis. 1996;55(7):442–9.
  34. De Chiara A, Pederzoli-Ribeil M, Mocek J, Candalh C, Mayeux P, Millet A, et al. Characterization of cytosolic proliferating cell nuclear antigen (PCNA) in neutrophils: antiapoptotic role of the monomer. J Leukoc Biol. 2013;94(4):723–31.
  35. Witko-Sarsat V, Rieu P, Descamps-Latscha B, Lesavre P, Halbwachs-Mecarelli L. Neutrophils: molecules, functions and pathophysiological aspects. Lab Invest. 2000;80(5):617–53.
  36. Bratton DL, Henson PM. Neutrophil clearance: when the party is over, clean-up begins. Trends Immunol. 2011;32(8):350–7.
  37. Miles K, Clarke DJ, Lu W, Sibinska Z, Beaumont PE, Davidson DJ, et al. Dying and necrotic neutrophils are anti-inflammatory secondary to the release of alpha-defensins. J Immunol. 2009;183(3):2122–32.
  38. Ravichandran KS. Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity. 2011;35(4):445–55.
  39. Kantari C, Pederzoli-Ribeil M, Amir-Moazami O, Gausson-Dorey V, Moura IC, Lecomte MC, et al. Proteinase 3, the Wegener autoantigen, is externalized during neutrophil apoptosis: evidence for a functional association with phospholipid scramblase 1 and interference with macrophage phagocytosis. Blood. 2007;110(12):4086–95.
  40. Park YJ, Liu G, Lorne EF, Zhao X, Wang J, Tsuruta Y, et al. PAI-1 inhibits neutrophil efferocytosis. Proc Natl Acad Sci U S A. 2008;105(33):11784–9.
  41. Elliott MR, Ravichandran KS. Clearance of apoptotic cells: implications in health and disease. J Cell Biol. 2010;189(7):1059–70.
  42. Gilroy DW, Lawrence T, Perretti M, Rossi AG. Inflammatory resolution: new opportunities for drug discovery. Nat Rev Drug Discov. 2004;3(5):401–16.
  43. Fadok VA, Bratton DL, Henson PM. Phagocyte receptors for apoptotic cells: recognition, uptake, and consequences. J Clin Invest. 2001;108(7):957–62.
  44. Esnault VL. Apoptosis: the central actor in the three hits that trigger anti-neutrophil cytoplasmic antibody-related systemic vasculitis. Nephrol Dial Transplant. 2002;17(10):1725–8.
  45. Roos A, Xu W, Castellano G, Nauta AJ, Garred P, Daha MR, et al. Mini-review: A pivotal role for innate immunity in the clearance of apoptotic cells. Eur J Immunol. 2004;34(4):921–9.
  46. Leitch AE, Haslett C, Rossi AG. Cyclin-dependent kinase inhibitor drugs as potential novel anti-inflammatory and pro-resolution agents. Br J Pharmacol. 2009;158(4):1004–16.
  47. Jennette JC, Xiao H, Falk RJ. Pathogenesis of vascular inflammation by anti-neutrophil cytoplasmic antibodies. J Am Soc Nephrol. 2006;17(5):1235–42.
  48. Witko-Sarsat V, Daniel S, Noel LH, Mouthon L. Neutrophils and B lymphocytes in ANCA-associated vasculitis. APMIS Suppl. 2009;(127):27–31.
  49. van Rossum AP, Limburg PC, Kallenberg CG. Activation, apoptosis, and clearance of neutrophils in Wegener’s granulomatosis. Ann N Y Acad Sci. 2005;1051:1–11.
  50. Abdgawad M, Gunnarsson L, Bengtsson A, Geborek P, Segelmark M, Hellmark T. Studies of mechanisms underlying the prolonged neutrophil survival in ANCA-Associated Systemic Vasculitis. Proceedings of the 14th International Vasculitis and ANCA Workshop; APMIS. 2009;117(suppl.127):abstract G5; 121.
  51. Harper L, Radford D, Plant T, Drayson M, Adu D, Savage CO. IgG from myeloperoxidase-antineutrophil cytoplasmic antibody-positive patients stimulates greater activation of primed neutrophils than IgG from proteinase 3–antineutrophil cytosplasmic antibody-positive patients. Arthritis Rheum. 2001;44(4):921–30.
  52. Morley A, Stohlman F, Jr. Cyclophosphamide-induced cyclical neutropenia. An animal model of a human periodic disease. N Engl J Med. 1970;282(12):643–6.
  53. Cross A, Bakstad D, Allen JC, Thomas L, Moots RJ, Edwards SW. Neutrophil gene expression in rheumatoid arthritis. Pathophysiology. 2005;12(3):191–202.
  54. Cross A, Barnes T, Bucknall RC, Edwards SW, Moots RJ. Neutrophil apoptosis in rheumatoid arthritis is regulated by local oxygen tensions within joints. J Leukoc Biol. 2006;80(3):521–8.
  55. Desaulniers P, Marois S, Pare G, Popa-Nita O, Gilbert C, Naccache PH. Characterization of an activation factor released from human neutrophils after stimulation by triclinic monosodium urate crystals. J Rheumatol. 2006;33(5):928–38.
  56. Cascao R, Rosario HS, Souto-Carneiro MM, Fonseca JE. Neutrophils in rheumatoid arthritis: More than simple final effectors. Autoimmun Rev. 2010;9(8):531–5.
  57. Gray M, Miles K, Salter D, Gray D, Savill J. Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. Proc Natl Acad Sci U S A. 2007;104(35):14080–5.
  58. Perruche S, Saas P. L14. Immunomodulatory properties of apoptotic cells. Presse Med. 2013;42(4 Pt 2):537–43.