Regulation of the neutrophil life span by apoptosis provides a fine balance between their function as effector cells of host defense and a safe turnover of these potentially harmful cells. Alterations of neutrophil apoptosis are associated with a number of diseases. As do other cell types, neutrophils possess components of both extrinsic and intrinsic apoptotic routes. The intrinsic pathway of apoptosis seems to be of major importance in neutrophils since they are programmed for a rapid spontaneous cell death. However, in neutrophils this mechanism of apoptosis has special features, probably due to peculiarities of neutrophil mitochondria, which are believed to be a core regulator of intrinsic cell death. A better understanding of mechanisms underlying neutrophil cell death would help to understand neutrophil physiology and contribute to the search of new approaches for handling of pathology related to disturbances in neutrophil apoptosis and also increase our knowledge of inflammation in general.

Klebanoff SJ, Clark RX: The Neutrophil: Function and Clinical Disorders. Amsterdam, North-Holland Publishing, 1978, p 313.
Weiss SJ: Tissue destruction by neutrophils. N Engl J Med 1989;320:365–376.
Whyte MK, Meagher LC, MacDermot J, Haslett C: Impairment of function in aging neutrophils is associated with apoptosis. J Immunol 1993;150:5124–5134.
Dransfield I, Stocks SC, Haslett C: Regulation of cell adhesion molecule expression and function associated with neutrophil apoptosis. Blood 1995;85:3264–3273.
Greenstein S, Barnard J, Zhou K, Fong M, Hendey B: Fas activation reduces neutrophil adhesion to endothelial cells. J Leukoc Biol 2000;68:715–722.
Kothakota S, Azuma T, Reinhard C, Klippel A, Tang J, Chu K, McGarry TJ, Kirschner MW, Koths K, Kwiatkowski DJ, Williams LT: Caspase-3-generated fragment of gelsolin: Effector of morphological change in apoptosis. Science 1997;278:294–298.
Whyte M, Renshaw S, Lawson R, Bingle C: Apoptosis and the regulation of neutrophil lifespan. Biochem Soc Trans 1999;27:802–807.
Haslett CHRI: Granulocyte apoptosis and its role in the resolution and control of lung inflammation. Am J Respir Crit Care Med 1999;160:5S–11S.
Ward I, Dransfield I, Chilvers ER, Haslett I, Rossi AG: Pharmacological manipulation of granulocyte apoptosis: Potential therapeutic targets. Trends Pharmacol Sci 1999;20:503–509.
Akgul C, Moulding DA, Edwards SW: Molecular control of neutrophil apoptosis. FEBS Lett 2001;487:318–322.
Watson RW: Redox regulation of neutrophil apoptosis. Antioxid Redox Signal 2002;4:97–104.
Takeda Y, Watanabe H, Yonehara S, Yamashita T, Saito S, Sendo F: Rapid acceleration of neutrophil apoptosis by tumor necrosis factor-α. Int Immunol 1993;5:691–694.
Watson RW, Redmond HP, Wang JH, Bouchier-Hayes D: Bacterial ingestion, tumor necrosis factor-α, and heat induce programmed cell death in activated neutrophils. Shock 1996;5:47–51.
Murray J, Barbara JA, Dunkley SA, Lopez AF, Van Ostade X, Condliffe AM, Dransfield I, Haslett C, Chilvers ER: Regulation of neutrophil apoptosis by tumor necrosis factor-α: Requirement for TNFR55 and TNFR75 for induction of apoptosis in vitro. Blood 1997;90:2772–2783.
Kettritz R, Gaido ML, Haller H, Luft FC, Jennette CJ, Falk RJ: Interleukin-8 delays spontaneous and tumor necrosis factor-α-mediated apoptosis of human neutrophils. Kidney Int 1998;53:84–91.
Yamashita K, Takahashi A, Kobayashi S, Hirata H, Mesner PW Jr, Kaufmann SH, Yonehara S, Yamamoto K, Uchiyama T, Sasada M: Caspases mediate tumor necrosis factor-α-induced neutrophil apoptosis and downregulation of reactive oxygen production. Blood 1999;93:674–685.
Weinmann P, Gaehtgens P, Walzog B: Bcl-XL- and Bax-α-mediated regulation of apoptosis of human neutrophils via caspase-3. Blood 1999;99:3106–3115.
Maianski NA, Roos D, Kuijpers TW: Tumor necrosis factor-α induces a caspase-independent death pathway in human neutrophils. Blood 2003;101:1987–1995.
Colotta F, Re F, Polentarutti N, Sozzani S, Mantovani A: Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products. Blood 1992;80:2012–2020.
Keel M, Ungethum U, Steckholzer U, Niederer E, Hartung T, Trentz O, Ertel W: Interleukin-10 counterregulates proinflammatory cytokine-induced inhibition of neutrophil apoptosis during severe sepsis. Blood 1997;90:3356–3363.
Van den Berg JM, Weyer S, Weening JJ, Roos D, Kuijpers TW: Divergent effects of tumor necrosis factor-α on apoptosis of human neutrophils. J Leukoc Biol 2001;69:467–473.
Salamone G, Giordano M, Trevani AS, Gamberale R, Vermeulen M, Schettinni J, Geffner JR: Promotion of neutrophil apoptosis by TNF-α. J Immunol 2001;166:3476–3483.
Cox G: IL-10 enhances resolution of pulmonary inflammation in vivo by promoting apoptosis of neutrophils. Am J Physiol 1996;271:L566–571.
Cox G, Austin RC: Dexamethasone-induced suppression of apoptosis in human neutrophils requires continuous stimulation of new protein synthesis. J Leukoc Biol 1997;61:224–230.
Cox G: Glucocorticoid treatment inhibits apoptosis of human neutrophils. J Immunol 1995;154;4719–4725.
Liles WC, Dale DC, Klebanoff SJ: Glucocorticoids inhibit apoptosis of human neutrophils. Blood 1995;86:3181–3188.
Meagher LC, Cousin JM, Seckl JR, Haslett C: Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J Immunol 1996;156:4422–4428.
Simon HU: Regulation of eosinophil and neutrophil apoptosis – Similarities and differences. Immunol Rev 2001;179:156–162.
Lee A, Whyte MK, Haslett C: Inhibition of apoptosis and prolongation of neutrophil functional longevity by inflammatory mediators. J Leukoc Biol 1993;54:283–288.
Watson RW, Rotstein OD, Parodo J, Bitar R, Marshall JC, William R, Watson G: The IL-1β-converting enzyme (caspase-1) inhibits apoptosis of inflammatory neutrophils through activation of IL-1β. J Immunol 1998;161:957–962.
Biffl WL, Moore EE, Moore FA, Barnett CC Jr, Silliman CC, Peterson VM: Interleukin-6 stimulates neutrophil production of platelet-activating factor. J Leukoc Biol 1996;59:569–574.
Savill J: Apoptosis in resolution of inflammation. J Leukoc Biol 1997;61:375–380.
Savill J, Vadok V: Corpse clearance defines the meaning of cell death. Nature 2000;407:784–788.
Dransfield I: An appetite for apoptotic cells? Controversies and challenges. Br J Haematol 2000;109:1–12.
Cory S, Adams JM: The Bcl-2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer 2002;2:647–656.
Krammer PH: CD95’s deadly mission in the immune system. Nature 2000;407:789–795.
Newmeyer DD, Ferguson-Miller S: Mitochondria: Releasing power for life and unleashing the machineries of death. Cell 2003;112:481–490.
Borregaard N, Herlin T: Energy metabolism of human neutrophils during phagocytosis. J Clin Invest 1982;70:550–557.
Fossati G, Moulding DA, Spiller DG, Moots RJ, White MRH, Edwards SW: The mitochondrial network of human neutrophils: Role in chemotaxis, phagocytosis, respiratory burst activation, and commitment to apoptosis. J Immunol 2003;170:1964–1972.
Peachman KK, Lyles DS, Baas DA: Mitochondria in eosinophils: Functional role in apoptosis but not respiration. Proc Natl Acad Sci USA 2001;98:1717–1722.
Maianski NA, Mul FPJ, van Buul JD, Roos D, Kuijpers TW: Granulocyte colony-stimulating factor inhibits the mitochondria-dependent activation of caspase-3 in neutrophils. Blood 2002;99:672–679.
Lavastre V, Pelletier M, Saller R, Hostanska K, Girard D: Mechanisms involved in spontaneous and Viscum album agglutinin-I-induced human neutrophil apoptosis: Viscum album agglutinin-I accelerates the loss of antiapoptotic Mcl-1 expression and the degradation of cytoskeletal paxillin and vimentin proteins via caspases. J Immunol 2002;168:1419–1427.
Pryde JG, Walker A, Rossi AG, Hannah S, Haslett C: Temperature-dependent arrest of neutrophil apoptosis. Failure of bax insertion into mitochondria at 15°C prevents the release of cytochrome c. J Biol Chem 2000;275:33574–33584.
Liu CY, Takemasa A, Liles WC, Goodman RB, Jonas M, Rosen H, Chi E, Winn RK, Harlan JM, Chuang PI: Broad-spectrum caspase inhibition paradoxically augments cell death in TNF-α-stimulated neutrophils. Blood 2003;101:295–304.
Murphy BM, O’Neill AJ, Adrain C, Watson RW, Martin SJ: The apoptosome pathway to caspase activation in primary human neutrophils exhibits dramatically reduced requirements for cytochrome c. J Exp Med 2003;197:625–632.
McDonald PP, Bovolenta C, Cassatella MA: Activation of distinct transcription factors in neutrophils by bacterial LPS, interferon-γ, and GM-CSF and the necessity to overcome the action of endogenous proteases. Biochemistry 1998;37:13165–13173.
Adrian C, Martin SJ: The mitochondrial apoptosome: A killer unleashed by the cytochrome seas. Trends Biochem Sci 2001;26:390–397.
Adams JM, Cory S: Apoptosomes: Engines for caspase activation. Curr Opin Cell Biol 2002;14:715–720.
Green DR, Evan GI: A matter of life and death. Cancer Cell 2002;1:19–30.
Leist M, Jaattela M: Four deaths and funeral: From caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2001;2:1–10.
Lockshin RA, Zakeri Z: Caspase-independent cell deaths. Curr Opin Cell Biol 2002;14:727–733.
Cauwels A, Janssen B, Waeytens A, Cuvelier C, Brouckaert P: Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2. Nat Immunol 2003;4:387–393.
Schulze-Osthoff K, Bakker AC, Vanhaesebroeck B, Beyaert R, Jacob WA, Fiers W: Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J Biol Chem 1992;267:5317–5323.
Goossens V, Grooten J, De Vos K, Fiers W: Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc Natl Acad Sci USA 1995;92:8115–8119.
Werner E, Werb Z: Integrins engage mitochondrial function for signal transduction by a mechanism dependent on Rho GTPases. J Cell Biol 2002;158:357–368.
Finkel T: Oxygen radicals and signaling. Curr Opin Cell Biol. 1998;10:248–253.
Nathan C: Specificity of a third kind: Reactive oxygen and nitrogen intermediates in cell signaling. J Clin Invest 2003;111:769–778.
Roos D, Curnutte JT: Chronic granulomatous disease; in Ochs HD, Smith CIE, Puck JM (eds): Primary Immunodeficiency Diseases. A Molecular and Genetic Approach. New York, Oxford University Press, 1999, pp 353–374.
Blouin E, Halbwachs-Mecarelli L, Rieu P: Redox regulation of β2-integrin CD11b/CD18 activation. Eur J Immunol 1999;29:3419–3431.
Lambeth JD: Nox/Duox family of nicotinamide adenine dinucleotide (phosphate) oxidases. Curr Opin Hematol 2002;9:11–17.
Roos D, Voetman AA, Meerhof LJ: Functional activity of enucleated human polymorphonuclear leukocytes. J Cell Biol 1983;97:368–377.
Korchak HM, Roos D, Giedd KN, Wynkoop EM, Vienne K, Rutherford LE, Buyon JP, Rich AM, Weissmann G: Granulocytes without degranulation: Neutrophil function in granule-depleted cytoplasts. Proc Natl Acad Sci USA 1983;80:4968–4972.
Martin SJ, Finucane DM, Amarante-Mendes GP, O’Brein GA, Green DR: Phosphatidylserine externalization during CD95-induced apoptosis of cells and cytoplasts requires ICE/CED-3 protease activity. J Biol Chem 1996;271:28753–28756.
Moulding DA, Akgul C, Derouet M, White MRH, Edwards SW: BCL-2 family expression in human neutrophils during delayed and accelerated apoptosis. J Leukoc Biol 2001;70:783–792.
Brach MA, deVos S, Gruss HJ, Herrmann F: Prolongation of survival of human polymorphonuclear neutrophils by granulocyte-macrophage colony-stimulating factor is caused by inhibition of programmed cell death. Blood 1992;80:2920–2924.
Suzuki K, Hasegawa T, Sakamoto C, Zhou YM, Hato F, Hino M, Tatsumi N, Kitagawa S: Cleavage of mitogen-activated protein kinases in human neutrophils undergoing apoptosis: Role in decreased responsiveness to inflammatory cytokines. J Immunol 2001;166:1185–1192.
Barinaga M: Apoptosis: Life-death balance within the cell. Science 1996;274:724.
Moulding DA, Quayle JA, Hart CA, Edwards SW: Mcl-1 expression in human neutrophils: Regulation by cytokines and correlation with cell survival. Blood 1998;92:2495–2502.
Van Der Vliet HJ, Wever PC, Van Diepen FN, Yong SL, Ten Berge IJ: Quantification of Bax/Bcl-2 ratios in peripheral blood lymphocytes, monocytes and granulocytes and their relation to susceptibility to anti-Fas (anti-CD95)-induced apoptosis. Clin Exp Immunol 1997;110:324–328.
Epling-Burnette PK, Zhong B, Bai F, Jiang K, Bailey RD, Garcia R, Jove R, Djeu JY, Loughran TP Jr, Wei S: Cooperative regulation of Mcl-1 by Janus kinase/stat and phosphatidylinositol 3-kinase contribute to granulocyte-macrophage colony-stimulating factor-delayed apoptosis in human neutrophils. J Immunol 2001;166:7486–7495.
Aprikyan AA, Liles WC, Park JR, Jonas M, Chi EY, Dale DC: Myelokathexis, a congenital disorder of severe neutropenia characterized by accelerated apoptosis and defective expression of bcl-x in neutrophil precursors. Blood 2000;95:320–327.
Aprikyan AA, Liles WC, Rodger E, Jonas M, Chi EY, Dale DC: Impaired survival of bone marrow hematopoietic progenitor cells in cyclic neutropenia. Blood 2001;97:147–153.
Aprikyan AA, Liles WC, Boxer LA, Dale DC: Mutant elastase in pathogenesis of cyclic and severe congenital neutropenia. J Pediatr Hematol Oncol 2002;24:784–786.
Mackey MC, Aprikyan AA, Dale DC: The rate of apoptosis in post-mitotic neutrophil precursors of normal and neutropenic humans. Cell Prolif 2003;36:27–34.
Aprikyan AA, Carlsson G, Stein S, Oganesian A, Fadeel B; Dale DC, Palmblad J, Henter JI: Neutrophil elastase mutations in severe congenital neutropenia patients of the original Kostmann family. Blood 2003;2002–2004.
Papadaki HA, Eliopoulos AG, Kosteas T, Gemetzi C, Damianaki A, Koutala H, Bux J, Eliopoulos GD: Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells. Blood 2003;101:2591–2600.
Liu JH, Wei S, Lamy T, Epling-Burnette PK, Starkebaum G, Djeu JY, Loughran TP: Chronic neutropenia mediated by Fas ligand. Blood 2000;95:3219–3222.
Kuijpers TW, Maianski NA, Tool AT et al: Apoptotic neutrophils in the circulation of patients with glycogen storage disease type 1b (GSD1b). Blood 2003;101:5021–5024.
Leuzzi R, Banhegyi G, Kardon T, Marcolongo P, Capecchi PL, Burger HJ, Angelo Benedetti A, Fulceri R: Inhibition of microsomal glucose-6-phosphate transport in human neutrophils results in apoptosis: A potential explanation for neutrophil dysfunction in glycogen storage disease type 1b. Blood 2003;101:2391–2397.
Kusaba N, Kumashiro R, Ogata H, Sata M, Tanikawa K: In vitro study of neutrophil apoptosis in liver cirrhosis. Intern Med 1998;37:11–17.
Shive MS, Salloum ML, Anderson JM: Shear stress-induced apoptosis of adherent neutrophils: A mechanism for persistence of cardiovascular device infections. Proc Natl Acad Sci USA 2000;97:6710–6715.
Chitnis D, Dickerson C, Munster AM, Winchurch RA: Inhibition of apoptosis in polymorphonuclear neutrophils from burn patients. J Leukoc Biol 1996;59:835–839.
Ertel W, Keel M, Infanger M, Ungethum U, Steckholzer U, Trentz O: Circulating mediators in serum of injured patients with septic complications inhibit neutrophil apoptosis through up-regulation of protein-tyrosine phosphorylation. J Trauma 1998;44:767–775.
Jimenez MF, Watson RW, Parodo J, Evans D, Foster D, Steinberg M, Rotstein OD, Marshall JC: Dysregulated expression of neutrophil apoptosis in the systemic inflammatory response syndrome. Arch Surg 1997;132:1263–1269.
Kobayashi E, Yamauchi H: Interleukin-6 and a delay of neutrophil apoptosis after major surgery. Arch Surg 1997;132:209–210.
Goodman ER, Kleinstein E, Fusco AM, Quinlan DP, Lavery R, Livingston DH, Deitch EA, Hauser CJ: Role of interleukin-8 in the genesis of acute respiratory distress syndrome through an effect on neutrophil apoptosis. Arch Surg 1998;133:1234–1239.
Sendo F, Tsuchida H, Takeda Y, Gon S, Takei H, Kato T, Hachiya O, Watanabe H: Regulation of neutrophil apoptosis – Its biological significance in inflammation and the immune response. Hum Cell 1996;9:215–222.
Kobayashi S, Yamashita K, Takeoka T, Ohtsuki T, Suzuki Y, Takahashi R, Yamamoto K, Kaufmann SH, Uchiyama T, Sasada M, Takahashi A: Calpain-mediated X-linked Inhibitor of apoptosis degradation in neutrophil apoptosis and its impairment in chronic neutrophilic leukemia. J Biol Chem 2002;277:33968–33977.
Hasegawa T, Suzuki K, Sakamoto C, Ohta K, Nishiki S, Hino M, Tatsumi N, Kitagawa S: Expression of the inhibitor of apoptosis (IAP) family members in human neutrophils: Up-regulation of cIAP2 by granulocyte colony-stimulating factor and overexpression of cIAP2 in chronic neutrophilic leukemia. Blood 2003:101:1164–1171.
Gisslinger H, Kurzrock R, Wetzler M, Tucker S, Kantarjian H, Robertson B, Talpaz M: Apoptosis in chronic myelogenous leukemia: Studies of stage-specific differences. Leuk Lymphoma 1997;25:121–133.
Jones ST, Denton J, Holt PJ, Freemont AJ: Possible clearance of effete polymorphonuclear leucocytes from synovial fluid by cytophagocytic mononuclear cells: Implications for pathogenesis and chronicity in inflammatory arthritis. Ann Rheum Dis 1993;52:121–126.
Courtney PA, Crockard AD, Williamson K, Irvine AE, Kennedy RJ, Bell AL: Increased apoptotic peripheral blood neutrophils in systemic lupus erythematosus: Relations with disease activity, antibodies to double-stranded DNA, and neutropenia. Ann Rheum Dis 1999;58:309–314.
McConnell JR, Crockard AD, Cairns AP, Bell AL: Neutrophils from systemic lupus erythematosus patients demonstrate increased nuclear DNA damage. Clin Exp Rheumatol 2002;20:653–660.
Vandivier RW, Fadok VA, Hoffmann PR, Bratton DL, Penvari C, Brown KK, Brain JD, Accurso FJ, Henson PM: Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. J Clin Invest 2002;109:661–670.
Colamussi ML, White MR, Crouch E, Hartshorn KL: Influenza A virus accelerates neutrophil apoptosis and markedly potentiates apoptotic effects of bacteria. Blood 1999;93:2395–2403.
Lundqvist-Gustafsson H, Norrman S, Nilsson J, Wilsson A: Involvement of p38-mitogen-activated protein kinase in Staphylococcus aureus-induced neutrophil apoptosis. J Leukoc Biol 2001;70:642–648.
Yamamoto A, Taniuchi S, Tsuji S, Hasui M, Kobayashi Y: Role of reactive oxygen species in neutrophil apoptosis following ingestion of heat-killed Staphylococcus aureus. Clin Exp Immunol 2002;129:479–484.
Perskvist N, Long M, Stendahl O, Zheng L: Mycobacterium tuberculosis promotes apoptosis in human neutrophils by activating caspase-3 and altering expression of Bax/Bcl-xL via an oxygen-dependent pathway. J Immunol 2002;168:6358–6365.
Rotstein D, Parodo J, Taneja R, Marshall JC: Phagocytosis of Candida albicans induces apoptosis of human neutrophils. Shock 2000;14:278–283.
Tschopp J, Martinon F, Burns K: NALPs: A novel protein family involved in inflammation. Nat Rev Mol Cell Biol 2003;4:95–104.
Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR: The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme. Cell 1993;75:641–652.
Rowe SJ, Allen L, Ridger VC, Hellewell PG, Whyte MK: Caspase-1-deficient mice have delayed neutrophil apoptosis and a prolonged inflammatory response to lipopolysaccharide-induced acute lung injury. J Immunol 2002;169:6401–6407.
Santos-Beneit AM, Mollinedo F: Expression of genes involved in initiation, regulation and execution of apoptosis in human neutrophils and during neutrophil differentiation of HL-60 cells. J Leukoc Biol 2000;67:712–724.
Miwa K, Asano M, Horai R, Iwakura Y, Nagata S, Suda T: Caspase 1-independent IL-1β release and inflammation induced by the apoptosis inducer Fas ligand. Nat Med 1998;4:1287–1292.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.