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  • Review Article
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Neutrophil recruitment and function in health and inflammation

Nature Reviews Immunology volume 13, pages 159–175 (2013)Cite this article

Subjects

Key Points

  • The current view of the neutrophil as a short-lived, homogeneous cell type with a role limited to the elimination of pathogens during the innate immune response has begun to change. Recent studies have revealed that the lifespan of a neutrophil in circulation might be much longer, and that differential subpopulations of neutrophils and their reservoirs (marginal pools) might exist (although it still remains to be determined whether these subpopulations are functional or lineage-restricted).

  • The classical cascade of neutrophil recruitment has been updated recently to reflect our better understanding of how this process occurs in the blood under shear stress conditions (for example, neutrophils have been found to form tethers and slings to anchor themselves to the vasculature). In addition, our understanding has improved regarding what are preferable sites of neutrophil extravasation. It is also now clear that there are exceptions to this classical cascade in a number of organs, such as the liver, lung and brain, where some steps of the cascade do not occur and/or different molecules are used by neutrophils. Furthermore, we recognize there might be differences between sterile and infectious inflammation.

  • Once extravasated, neutrophils follow a hierarchy of chemotactic molecules to reach the site of inflammation, following first 'intermediate' chemoattractants (endogenous chemokines) and then later 'end-target' chemoattractants (bacterial peptides or complement components). The process of chemotaxis is controlled by multiple intracellular signalling pathways (mitogen-activated protein kinase-dependent) controlling 'go' and 'stop' signals.

  • Despite the pre-existing dogma that neutrophils leave the vasculature and die, it has been revealed that some extravasated neutrophils might re-enter circulation, leading to the dissemination of inflammation to other organs and subsequent tissue injury. In other cases, transmigrating cells may play an important part in the resolution of inflammation. In fact, neutrophils were shown to participate in wound healing and to actively limit self-recruitment through the release of endogenous molecules that inhibit integrin activation or cytoskeletal changes.

  • Newly described roles of neutrophils cover their involvement in adaptive immunity by controlling the activation of T and B cells, and through the presentation of antigens to professional antigen-presenting cells in lymph nodes.

  • Neutrophil extracellular trap (NET) formation, a strategy of pathogen eradication discovered less than a decade ago, has now been described to occur in vivo not only during acute (bacterial or viral) inflammation but also in numerous pathological conditions, such as autoimmune diseases, vascular diseases and cancer. Recently described mechanisms of NET formation indicate that neutrophils releasing NETs in vivo do not immediately die but rather keep performing functions such as chemotaxis and phagocytosis.

Abstract

Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti-inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites.

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Figure 1: The updated classical neutrophil recruitment cascade.
Figure 2: Mechanisms of formation and engagement of tethers and slings by rolling neutrophils.
Figure 3: Migrating neutrophils actively choose sites of transmigration.

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Acknowledgements

The work in the authors' laboratory is supported by operating grants and a group grant from the Canadian Institutes for Health Research, as well as by the Canadian Foundation for Innovation. P.K. is an Alberta Heritage Foundation for Medical Research (AIHS) Scientist and the Snyder Chair in Critical Care Medicine. E.K. is supported by an FP7-PEOPLE-2010-IOF grant (No. 273340) from the European Union.

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  1. Snyder Institute of Infection, Immunity, and Inflammation, University of Calgary, T2N 4N1, Alberta, Canada

    Elzbieta Kolaczkowska & Paul Kubes

  2. Department of Physiology and Pharmacology, University of Calgary, T2N 4N1, Alberta, Canada

    Elzbieta Kolaczkowska & Paul Kubes

  3. Department of Evolutionary Immunology, Jagiellonian University, PL-30-387, Krakow, Poland

    Elzbieta Kolaczkowska

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Glossary

Liver X receptors

(LXRs). Oxysterol-activated nuclear receptors that regulate cholesterol homeostasis.

M1 macrophages

Classically activated macrophages that are characterized by a pro-inflammatory interleukin-12 (IL-12)hi IL-23hi IL-10low phenotype and express inducible nitric oxide synthase (iNOS).

M2 macrophages

Alternatively activated macrophages that are characterized by an anti-inflammatory and pro-reparatory phenotype. M2 macrophages are interleukin-12 (IL-12)low IL-23low IL-10hi and express arginase 1, the mannose receptor CD206 and the IL-4 receptor α-chain.

Invariant natural killer T cells

(iNKT cells). Types of T lymphocyte that express a T cell receptor with an invariant Vα14-Jα18 chain in mice (Vα24-Jα18 in humans) paired with limited Vβ chains. iNKT cells recognize lipid antigens presented by CD1d (an atypical MHC class I-like molecule).

Pericyte

An elongated cell that is embedded within the venular basement membrane and surrounds the endothelial cells of some capillaries and venules.

α-galactosylceramide

A lipid isolated from marine sponge Agelas mauritianus that is a CD1-dependent antigen for invariant natural killer T cells.

NLRP3 inflammasome

The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome of the NOD-like receptor family is a multiprotein complex that activates caspase 1, leading to the processing of pro-interleukin-1β and pro-interleukin-18.

Intracellular matrix

(ICM). Intracellular matrix (as opposed to extracellular matrix) is present in physiological conditions exclusively inside cells in either the cytosol or nucleus.

Specialized pro-resolving mediators

Lipid mediators that are synthesized from ω-3 poly-unsaturated fatty acids (distinct from classic eicosanoids (prostaglandins and leukotrienes)) and that act in an anti-inflammatory manner.

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

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