The neutrophil is one of the body's main cellular mediators of the destruction of microorganisms, and inevitably damages cells and tissues of the host. Neutrophil-mediated tissue destruction is most often a life-saving process, and the host relies on tissue injury as one of the main sources of information that launches inflammation and immunity.
Neutrophils make important contributions to the recruitment, activation and programming of dendritic cells and macrophages. In turn, the adaptive immune system controls the rate of neutrophil production in the bone marrow.
Neutrophils have important roles in healing wounds, including sterilization of microorganisms, generation of signals that slow the rate of accumulation of more neutrophils, and instigation of a macrophage-based programme that switches the state of damaged epithelium from pro-inflammatory and nonreplicative, to anti-inflammatory and replicative.
The two main innovations of innate immunity both involve distinctive forms of specificity: molecular specificity in the recognition of relatively invariant and widely distributed microbial macromolecules, and specific, covalent chemical reactions by reactive oxygen intermediates and reactive nitrogen intermediates with a subset of atoms shared by and critical to the function of diverse microbial molecules.
Two kinds of signals can exert binary control over the respiratory burst and degranulation: signals resulting from integrin ligation with extracellular-matrix proteins on cellular or acellular surfaces and signals transmitted through cell-surface receptors for inflammatory factors.
New pathways of tumor-necrosis factor (TNF) signal transduction in neutrophils are being characterized that open up a new way to think of anti-inflammatory therapy, for example, pathways involving TNF-induced increases in intracellular Ca2+ and the ensuing activation of a non-transmembrane form of adenylyl cyclase, termed soluble adenylyl cyclase.
Scientists who study neutrophils often have backgrounds in cell biology, biochemistry, haematology, rheumatology or infectious disease. Paradoxically, immunologists seem to have a harder time incorporating these host-defence cells into the framework of their discipline. The recent literature discussed here indicates that it is appropriate for immunologists to take as much interest in neutrophils as in their lymphohaematopoietic cousins with smooth nuclei. Neutrophils inform and shape immune responses, contribute to the repair of tissue as well as its breakdown, use killing mechanisms that enrich our concepts of specificity, and offer exciting opportunities for the treatment of neoplastic, autoinflammatory and autoimmune disorders.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Nathan, C. Inflammation: points of control. Nature 420, 846–852 (2002).
Nathan, C. Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signalling. J. Clin. Invest. 111, 769–778 (2003).
Henson, P. M. & Johnston, R. B. Jr. Tissue injury in inflammation. Oxidants, proteinases, and cationic proteins. J. Clin. Invest. 79, 669–674 (1987).
Weiss, S. J. Tissue destruction by neutrophils. N. Engl. J. Med. 320, 365–376 (1989).
Lekstrom-Himes, J. A. & Gallin, J. I. Immunodeficiency diseases caused by defects in phagocytes. N. Engl. J. Med. 343, 1703–1714 (2000).
Klebanoff, S. J. & Clark, R. A. The Neutrophil: Function and Clinical Disorders (Elsevier/North-Holland, Amsterdam, 1978).
Witko-Sarsat, V., Rieu, P., Descamps-Latscha, B., Lesavre, P. & Halbwachs-Mecarelli, L. Neutrophils: molecules, functions and pathophysiological aspects. Lab. Invest. 80, 617–653 (2000).
Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).
Medzhitov, R. & Janeway, C. A. Jr. Decoding the patterns of self and nonself by the innate immune system. Science 296, 298–300 (2002).
Backhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A. & Gordon, J. I. Host-bacterial mutualism in the human intestine. Science 307, 1915–1920 (2005).
Chertov, O. et al. Identification of human neutrophil-derived cathepsin G and azurocidin/CAP37 as chemoattractants for mononuclear cells and neutrophils. J. Exp. Med. 186, 739–747 (1997).
Bennouna, S., Bliss, S. K., Curiel, T. J. & Denkers, E. Y. Cross-talk in the innate immune system: neutrophils instruct recruitment and activation of dendritic cells during microbial infection. J. Immunol. 171, 6052–6058 (2003).
Tsuda, Y. et al. Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus. Immunity 21, 215–226 (2004).
Wittamer, V. et al. Neutrophil-mediated maturation of chemerin: a link between innate and adaptive immunity. J. Immunol. 175, 487–493 (2005).
van Gisbergen, K. P., Sanchez-Hernandez, M., Geijtenbeek, T. B. & van Kooyk, Y. Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between Mac-1 and DC-SIGN. J. Exp. Med. 201, 1281–1292 (2005).
Scapini, P. et al. 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 (2005).
Ethuin, F. et al. Human neutrophils produce interferon-γ upon stimulation by interleukin-12. Lab. Invest. 84, 1363–1371 (2004).
Schmielau, J. & Finn, O. J. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients. Cancer Res. 61, 4756–4760 (2001).
Heissig, B. et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109, 625–637 (2002).
Semerad, C. L., Liu, F., Gregory, A. D., Stumpf, K. & Link, D. C. G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity 17, 413–423 (2002).
Stark, M. A. et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285–294 (2005).
Diefenbach, A. et al. Type 1 interferon (IFNα/β) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite. Immunity 8, 77–87 (1998).
Dovi, J. V., Szpaderska, A. M. & DiPietro, L. A. Neutrophil function in the healing wound: adding insult to injury? Thromb. Haemost. 92, 275–280 (2004).
Martin, P. et al. Wound healing in the PU.1 null mouse — tissue repair is not dependent on inflammatory cells. Curr. Biol. 13, 1122–1128 (2003).
Singer, A. J. & Clark, R. A. Cutaneous wound healing. N. Engl. J. Med. 341, 738–746 (1999).
Roos, D. & Law, S. K. Hematologically important mutations: leukocyte adhesion deficiency. Blood Cells Mol. Dis. 27, 1000–1004 (2001).
Alon, R. & Etzioni, A. LAD-III, a novel group of leukocyte integrin activation deficiencies. Trends Immunol. 24, 561–566 (2003).
Nathan, C. F. Neutrophil activation on biological surfaces. Massive secretion of hydrogen peroxide in response to products of macrophages and lymphocytes. J. Clin. Invest. 80, 1550–1560 (1987).
Serhan, C. N. Novel ω-3-derived local mediators in anti-inflammation and resolution. Pharmacol. Ther. 105, 7–21 (2005).
Jin, F. Y., Nathan, C., Radzioch, D. & Ding, A. Secretory leukocyte protease inhibitor: a macrophage product induced by and antagonistic to bacterial lipopolysaccharide. Cell 88, 417–426 (1997).
Zhu, J. et al. Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair. Cell 111, 867–878 (2002).
Grobmyer, S. R. et al. Secretory leukocyte protease inhibitor, an inhibitor of neutrophil activation, is elevated in serum in human sepsis and experimental endotoxemia. Crit. Care Med. 28, 1276–1282 (2000).
He, Z., Ong, C. H., Halper, J. & Bateman, A. Progranulin is a mediator of the wound response. Nature Med. 9, 225–229 (2003).
Klebanoff, S. J. Myeloperoxidase: friend and foe. J. Leukoc. Biol. 77, 598–625 (2005).
Hedrick, S. M. The acquired immune system: a vantage from beneath. Immunity 21, 607–615 (2004).
Casanova, J. L. & Abel, L. Inborn errors of immunity to infection: the rule rather than the exception. J. Exp. Med. 202, 197–201 (2005).
Nathan, C. The moving frontier in nitric oxide-dependent signalling. Sci. STKE 2 Nov 2004 (10.1126/stke. 2572004pe2572052).
Nathan, C. Nitric oxide as a secretory product of mammalian cells. FASEB. J. 6, 3051–3064 (1992).
Tonks, N. K. Redox redux: revisiting PTPs and the control of cell signalling. Cell 121, 667–670 (2005).
Li, Y., Karlin, A., Loike, J. D. & Silverstein, S. C. A critical concentration of neutrophils is required for effective bacterial killing in suspension. Proc. Natl Acad. Sci. USA 99, 8289–8294 (2002).
Savill, J. & Haslett, C. Granulocyte clearance by apoptosis in the resolution of inflammation. Semin. Cell Biol. 6, 385–393 (1995).
Peyssonnaux, C. et al. HIF-1α expression regulates the bactericidal capacity of phagocytes. J. Clin. Invest. 115, 1806–1815 (2005).
Walmsley, S. R. et al. Hypoxia-induced neutrophil survival is mediated by HIF-1α-dependent NF-κB activity. J. Exp. Med. 201, 105–115 (2005).
Jonsson, H., Allen, P. & Peng, S. L. Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis. Nature Med. 11, 666–671 (2005).
Altznauer, F. et al. Inflammation-associated cell cycle-independent block of apoptosis by survivin in terminally differentiated neutrophils. J. Exp. Med. 199, 1343–1354 (2004).
Flo, T. H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004).
Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).
Striz, I. & Trebichavsky, I. Calprotectin- a pleiotropic molecule in acute and chronic inflammation. Physiol. Res. 53, 245–253 (2004).
Wright, G. W., Ooi, C. E., Weiss, J. & Elsbach, P. Purification of a cellular (granulocyte) and an extracellular (serum) phospholipase A2 that participate in the destruction of Escherichia coli in a rabbit inflammatory exudate. J. Biol. Chem. 265, 6675–6681 (1990).
Faurschou, M. & Borregaard, N. Neutrophil granules and secretory vesicles in inflammation. Microbes Infect. 5, 1317–1327 (2003).
Selsted, M. E. & Ouellette, A. J. Mammalian defensins in the antimicrobial immune response. Nature Immunol. 6, 551–557 (2005).
Weiss, J., Elsbach, P., Olsson, I. & Odeberg, H. Purification and characterization of a potent bactericidal and membrane active protein from the granules of human polymorphonuclear leukocytes. J. Biol. Chem. 253, 2664–2672 (1978).
Campanelli, D., Detmers, P. A., Nathan, C. F. & Gabay, J. E. Azurocidin and a homologous serine protease from neutrophils. Differential antimicrobial and proteolytic properties. J. Clin. Invest. 85, 904–915 (1990).
Pereira, H. A., Shafer, W. M., Pohl, J., Martin, L. E. & Spitznagel, J. K. CAP37, a human neutrophil-derived chemotactic factor with monocyte specific activity. J. Clin. Invest. 85, 1468–1476 (1990).
McCord, J. M. & Fridovich, I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J. Biol. Chem. 244, 6049–6055 (1969).
Babior, B. M., Kipnes, R. S. & Curnutte, J. T. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J. Clin. Invest. 52, 741–744 (1973).
Lambeth, J. D. NOX enzymes and the biology of reactive oxygen. Nature Rev. Immunol. 4, 181–189 (2004).
Good, R. A. et al. Fatal (chronic) granulomatous disease of childhood: a hereditary defect of leukocyte function. Semin. Hematol. 5, 215–254 (1968).
Reeves, E. P. et al. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 416, 291–297 (2002).
Roos, D., van Bruggen, R. & Meischl, C. Oxidative killing of microbes by neutrophils. Microbes Infect. 5, 1307–1315 (2003).
Shiloh, M. U. et al. Phenotype of mice and macrophages deficient in both phagocyte oxidase and inducible nitric oxide synthase. Immunity 10, 29–38 (1999).
Staudinger, B. J., Oberdoerster, M. A., Lewis, P. J. & Rosen, H. mRNA expression profiles for Escherichia coli ingested by normal and phagocyte oxidase-deficient human neutrophils. J. Clin. Invest. 110, 1151–1163 (2002).
Liu, G. Y. et al. Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity. J. Exp. Med. 202, 209–215 (2005).
Nathan, C. F. Respiratory burst in adherent human neutrophils: triggering by colony-stimulating factors CSF–GM and CSF–G. Blood 73, 301–306 (1989).
Wolpe, S. D. et al. Macrophages secrete a novel heparin-binding protein with inflammatory and neutrophil chemokinetic properties. J. Exp. Med. 167, 570–581 (1988).
Nathan, C. et al. Cytokine-induced respiratory burst of human neutrophils: dependence on extracellular matrix proteins and CD11/CD18 integrins. J. Cell. Biol. 109, 1341–1349 (1989).
Nathan, C. & Sporn, M. Cytokines in context. J. Cell Biol. 113, 981–986 (1991).
Blouin, E., Halbwachs-Mecarelli, L. & Rieu, P. Redox regulation of β2-integrin CD11b/CD18 activation. Eur. J. Immunol. 29, 3419–3431 (1999).
Mocsai, A., Ligeti, E., Lowell, C. A. & Berton, G. Adhesion-dependent degranulation of neutrophils requires the Src family kinases Fgr and Hck. J. Immunol. 162, 1120–1126 (1999).
Fuortes, M., Melchior, M., Han, H., Lyon, G. J. & Nathan, C. Role of the tyrosine kinase pyk2 in the integrin-dependent activation of human neutrophils by TNF. J. Clin. Invest. 104, 327–335 (1999).
Mocsai, A., Zhou, M., Meng, F., Tybulewicz, V. L. & Lowell, C. A. Syk is required for integrin signalling in neutrophils. Immunity 16, 547–558 (2002).
Yan, S. R., Huang, M. & Berton, G. Signalling by adhesion in human neutrophils: activation of the p72syk tyrosine kinase and formation of protein complexes containing p72syk and Src family kinases in neutrophils spreading over fibrinogen. J. Immunol. 158, 1902–1910 (1997).
Korchak, H. M. & Kilpatrick, L. E. TNFα elicits association of PI3-kinase with the p60TNFR and activation of PI3-kinase in adherent neutrophils. Biochem. Biophys. Res. Commun. 281, 651–656 (2001).
Zhao, T., Benard, V., Bohl, B. P. & Bokoch, G. M. The molecular basis for adhesion-mediated suppression of reactive oxygen species generation by human neutrophils. J. Clin. Invest. 112, 1732–1740 (2003).
Gakidis, M. A. et al. Vav GEFs are required for β2 integrin-dependent functions of neutrophils. J. Cell Biol. 166, 273–282 (2004).
Fuortes, M., Jin, W. W. & Nathan, C. Adhesion-dependent protein tyrosine phosphorylation in neutrophils treated with tumour necrosis factor. J. Cell Biol. 120, 777–784 (1993).
Fuortes, M., Jin, W. W. & Nathan, C. β2 integrin-dependent tyrosine phosphorylation of paxillin in human neutrophils treated with tumour necrosis factor. J. Cell Biol. 127, 1477–1483 (1994).
Nathan, C., Xie, Q. W., Halbwachs-Mecarelli, L. & Jin, W. W. Albumin inhibits neutrophil spreading and hydrogen peroxide release by blocking the shedding of CD43 (sialophorin, leukosialin). J. Cell Biol. 122, 243–256 (1993).
Raptis, S. Z., Shapiro, S. D., Simmons, P. M., Cheng, A. M. & Pham, C. T. Serine protease cathepsin G regulates adhesion-dependent neutrophil effector functions by modulating integrin clustering. Immunity 22, 679–691 (2005).
Richter, J., Ng-Sikorski, J., Olsson, I. & Andersson, T. Tumour necrosis factor-induced degranulation in adherent human neutrophils is dependent on CD11b/CD18-integrin-triggered oscillations of cytosolic free Ca2+. Proc. Natl Acad. Sci. USA 87, 9472–9476 (1990).
Schumann, M. A., Gardner, P. & Raffin, T. A. Recombinant human tumour necrosis factor α induces calcium oscillation and calcium-activated chloride current in human neutrophils. The role of calcium/calmodulin-dependent protein kinase. J. Biol. Chem. 268, 2134–2140 (1993).
Han, H. et al. Calcium-sensing soluble adenylyl cyclase mediates TNF signal transduction in human neutrophils. J. Exp. Med. 202, 353–361 (2005).
Bengtsson, T. et al. Actin dynamics in human neutrophils during adhesion and phagocytosis is controlled by changes in intracellular free calcium. Eur. J. Cell. Biol. 62, 49–58 (1993).
Han, H., Fuortes, M. & Nathan, C. Critical role of the carboxyl terminus of proline-rich tyrosine kinase (Pyk2) in the activation of human neutrophils by tumour necrosis factor: separation of signals for the respiratory burst and degranulation. J. Exp. Med. 197, 63–75 (2003).
Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).
Rothstein, J. L. & Schreiber, H. Synergy between tumour necrosis factor and bacterial products causes hemorrhagic necrosis and lethal shock in normal mice. Proc. Natl Acad. Sci. USA 85, 607–611 (1988).
Tepper, R. I., Pattengale, P. K. & Leder, P. Murine interleukin-4 displays potent anti-tumour activity in vivo. Cell 57, 503–512 (1989).
Stoppacciaro, A. et al. Regression of an established tumour genetically modified to release granulocyte colony-stimulating factor requires granulocyte–T-cell cooperation and T cell-produced interferon γ. J. Exp. Med. 178, 151–161 (1993).
Soiffer, R. et al. Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumour immunity in patients with metastatic melanoma. Proc. Natl Acad. Sci. USA 95, 13141–13146 (1998).
Minasian, L. M. et al. Hemorrhagic tumour necrosis during a pilot trial of tumour necrosis factor-α and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma. Blood 83, 56–64 (1994).
Feagan, B. G. et al. Treatment of ulcerative colitis with a humanized antibody to the α4β7 integrin. N. Engl. J. Med. 352, 2499–2507 (2005).
Berger, J. R. & Koralnik, I. J. Progressive multifocal leukoencephalopathy and natalizumab — unforeseen consequences. N. Engl. J. Med. 353, 414–416 (2005).
Langer-Gould, A., Atlas, S. W., Green, A. J., Bollen, A. W. & Pelletier, D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N. Engl. J. Med. 353, 375–381 (2005).
Kleinschmidt-DeMasters, B. K. & Tyler, K. L. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon β-1a for multiple sclerosis. N. Engl. J. Med. 353, 369–374 (2005).
Luisetti, M. et al. MR889, a neutrophil elastase inhibitor, in patients with chronic obstructive pulmonary disease: a double-blind, randomized, placebo-controlled clinical trial. Eur. Respir. J. 9, 1482–1486 (1996).
de Garavilla, L. et al. A novel, potent dual inhibitor of the leukocyte proteases cathepsin G and chymase: molecular mechanisms and anti-inflammatory activity in vivo. J. Biol. Chem. 280, 18001–18007 (2005).
I thank A. Ding, M. Fuortes, W. A. Muller and J. Upshaw for critical reviews and apologize that the scope of the topic prevented citation of many important studies. The Department of Microbiology and Immunology acknowledges the support of the William Randolph Hearst Foundation.
The author declares no competing financial interests.
- Danger theory
A theory that the trigger for mounting an immune response consists of an injury to host cells, resulting in the release of alarm signals that activate antigen-presenting cells.
- Pattern-recognition theory
A theory that the trigger for mounting an immune response consists of the recognition of 'microbial non-self' molecules by receptors expressed by innate immune cells.
A dendritic-cell-attracting chemokine that is generated by neutrophil-dependent proteolytic activation of its precursor. Chemerin does not yet have a 'chemokine ligand' designation.
- Plasmacytoid DCs
Immature dendritic cells (DCs) with a morphology resembling that of plasma cells. Plasmacytoid DCs produce type I interferons in response to viral infection.
A collection of liquefied tissue containing many living or dead neutrophils and bacteria.
- Latent form
A form in which activity is not yet expressed, pending activation by an event such as redistribution from a particular compartment or proteolytic processing.
Biologically active compounds that are primarily derived from arachidonic acid, in part through cyclooxygenases and lipoxygenases, including prostaglandins, prostacyclins, thromboxanes, leukotrienes and lipoxins.
- Reduction of oxygen
Donation of electrons to molecular oxygen. Donation of up to three electrons gives rise to reactive oxygen intermediates (ROIs), whereas donation of four electrons gives rise to water. The term 'intermediate' in ROI refers to oxygen whose reduction state is intermediate between that of oxygen (O2) and water (H2O).
A lipid whose exposure on the outer leaflet of the plasma membrane generally correlates with apoptosis of the cell and promotes its uptake by other cells.
Low-molecular-weight bacterial compounds that chelate iron and deliver it to the bacterium through specific receptors.
Staining with azure (blue) components of the Romanowski-type stains used in standard evaluations of haematological specimens. In neutrophils, the earliest-formed set of granules, which contain many antibiotic proteins and proteases, are azurophilic.
A fungal metabolite that inhibits actin polymerization. Cytochalasin has been widely used in vitro to promote activation of neutrophils studied in suspension.
- Flavoprotein inhibitor
A compound that inhibits enzymes whose activity depends on their flavin cofactor(s). Diphenylene iodonium does so through its structural resemblance to a portion of the flavin molecule.
One of many small zones that form at the surface of a leukocyte as it adheres to a substratum, where integrins, integrin-binding proteins and termini of actin microfilaments cluster.
Linked with N-acetylneuraminic acid.
- Tumour-lysis syndrome
The immediate medical consequences of rapid destruction of large numbers of tumour cells, including the release of their intracellular potassium ions.
- Leukocyte-adhesion deficiency
(LAD). A rare hereditary disease that is characterized by recurrent infection and delayed wound healing as a consequence of defective leukocyte adhesion. LAD type I is caused by mutations of β2-integrin; LAD type II is caused by a defect in fucose metabolism that results in a failure to express sialyl-Lewis X, the ligand for endothelial-cell (E)-selectin and platelet (P)-selectin.
- Chronic granulomatous disease
A genetic deficiency of phagocyte oxidase (phox), associated with recurrent, life-threatening bacterial and fungal infections.
About this article
Cite this article
Nathan, C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 6, 173–182 (2006). https://doi.org/10.1038/nri1785
Impairment of neutrophil functions and homeostasis in COVID-19 patients: association with disease severity
Critical Care (2022)
Single-cell analysis of skin immune cells reveals an Angptl4-ifi20b axis that regulates monocyte differentiation during wound healing
Cell Death & Disease (2022)
Possible Interaction of Nonsteroidal Anti-inflammatory Drugs Against NF-κB- and COX-2-Mediated Inflammation: In Silico Probe
Applied Biochemistry and Biotechnology (2022)
Discover Oncology (2022)
Irish Journal of Medical Science (1971 -) (2022)