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Neutrophils and immunity: challenges and opportunities

Key Points

  • 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.

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Figure 1: Neutrophils interact with monocytes, dendritic cells, T cells and B cells in a bidirectional, multi-compartmental manner.
Figure 2: Neutrophils have a key role in wound healing both by controlling microbial contamination and by attracting monocytes and/or macrophages.
Figure 3: Neutrophils deliver multiple anti-microbial molecules.
Figure 4: Neurophils spread and reorganize their cytoskeleton after activation by dual stimuli through integrins and cytokine receptors.
Figure 5: Signalling proceeds through parallel, as well as intersecting, pathways in adherent neutrophils responding to tumour-necrosis factor.
Figure 6: Interdependence of the two main classes of neutrophil tissue-damaging products creates opportunities for anti-inflammatory strategies.


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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.

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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.

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Nathan, C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 6, 173–182 (2006).

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