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Neutrophils in the activation and regulation of innate and adaptive immunity

Key Points

  • Neutrophils have long been viewed as short-lived effector cells of the innate immune system, with a primary role in resistance against extracellular pathogens and in acute inflammation.

  • Neutrophils express a vast repertoire of pattern recognition receptors and in response to signals undergo functional reprogramming. In addition to classical antimicrobial molecules (such as reactive oxygen intermediates), the effector repertoire of neutrophils includes an array of cytokines and chemokines, components of the humoral arm of innate immunity (such as pentraxin 3) and the formation of neutrophil extracellular traps. Thus, the participation of these 'unsung heroes' to mechanisms of innate resistance goes well beyond the production of microorganism- and tissue-damaging molecules, to include a diverse, highly regulated, customized production of cytokines and antibody-like soluble pattern recognition molecules, as well as the release of neutrophil extracellular traps.

  • Once recruited into tissues, neutrophils engage in complex bidirectional interactions with macrophages, mesenchymal stem cells, dendritic cells, natural killer cells, and B and T cells.

  • In particular, neutrophils contribute to the activation, orientation and expression of adaptive immune responses.

  • Given their role as a component of innate and adaptive responses, it is not surprising that neutrophils have emerged as important players in the pathogenesis of numerous disorders, including infection caused by intracellular pathogens, autoimmunity, chronic inflammation and cancer.

  • These new perspectives raise the issue of targeting neutrophils as a therapeutic strategy in immunopathology.

Abstract

Neutrophils have long been viewed as the final effector cells of an acute inflammatory response, with a primary role in the clearance of extracellular pathogens. However, more recent evidence has extended the functions of these cells. The newly discovered repertoire of effector molecules in the neutrophil armamentarium includes a broad array of cytokines, extracellular traps and effector molecules of the humoral arm of the innate immune system. In addition, neutrophils are involved in the activation, regulation and effector functions of innate and adaptive immune cells. Accordingly, neutrophils have a crucial role in the pathogenesis of a broad range of diseases, including infections caused by intracellular pathogens, autoimmunity, chronic inflammation and cancer.

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Figure 1: Neutrophils crosstalk with immune and non-immune cells in inflamed tissues and lymph nodes.
Figure 2: Crosstalk between neutrophils, NK cells and SLAN+ DCs.
Figure 3: Interplay between neutrophils and T cells.
Figure 4: The role of neutrophils in the resolution of inflammation.
Figure 5: Tumour-associated neutrophils.

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Acknowledgements

This work is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), special project 5 × 1000 and the European Research Council (to A.M.); S.J. is the recipient of a Mario e Valeria Rindi Fellowship from AIRC; M.A.C. is supported by Fondazione Cariverona and AIRC. We apologize to those colleagues whose work could not be cited here owing to space limitations.

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Glossary

Granules

Neutrophils store an assortment of molecules in three types of granule (primary, secondary and tertiary). Primary granules are characterized by the accumulation of antimicrobial proteins and proteases, whereas secondary granules and tertiary granules are characterized by a high content of lactoferrin and gelatinase, respectively. In addition, secretory vesicles contain a reservoir of membrane-associated proteins.

Reactive oxygen intermediates

(ROI). In the context of this Review, this term refers to various reactive oxygen species, including superoxide anions produced by phagocytes via the activation of the NADPH oxidase enzymatic system, and other compounds derived from superoxide anion metabolism, such as hydrogen peroxide and hydroxyl radicals. ROI are crucial for the antimicrobial activity of neutrophils.

MicroRNAs

Single-stranded RNA molecules of approximately 21–23 nucleotides in length that are thought to regulate the expression of other genes.

N-formyl peptides

Bacteria initiate protein synthesis with N-formylmethionine, a modified form of the amino acid methionine. The only eukaryotic proteins that contain N-formylmethionine, and are therefore N-formylated, are those encoded by mitochondria.

Pattern recognition receptor

A germline-encoded receptor that recognizes unique and essential structures that are present in microorganisms, but absent from the host. In vertebrates, signalling through these receptors leads to the production of pro-inflammatory cytokines and chemokines and to the expression of co-stimulatory molecules by antigen-presenting cells.

Inflammasome

A molecular complex of several proteins — including members of the NOD-like receptor family — that upon assembly cleaves pro-interleukin-1 β (pro-IL-1β) and pro-IL-18, thereby producing the active cytokines.

Osteoclastogenesis

A process whereby haematopoietic stem cells differentiate into multinucleated osteoclasts with bone-resorbing activity.

Complement cascade

There are three independent pathways that can lead to the activation of the complement cascade. The classical pathway is activated via C1q binding to immune complexes; the alternative pathway is triggered by direct C3 activation; and the lectin pathway is initiated by the interaction of mannose-binding lectin with the surface of microorganisms.

NETosis

A form of cell death that differs from classical apoptosis and necrosis, and that occurs during the formation of neutrophil extracellular traps.

Ectosomes

Large membrane vesicles (>100nm diameter) that are secreted by budding or shedding from the plasma membrane.

SLAN

(6-sulpho LacNAc). A carbohydrate modification of P-selectin glycoprotein ligand 1 (PSGL1). SLAN is expressed by a subset of dendritic cells found in human blood and is recognized by the monoclonal antibody MDC8.

Resolvins

Lipid mediators that are induced in the resolution phase following acute inflammation. They are synthesized from the essential omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid.

Eat-me signals

Signals emitted by dying cells to facilitate their recognition and phagocytosis by neighbouring healthy cells.

Chronic obstructive pulmonary disease

(COPD). A group of diseases characterized by the pathological limitation of airflow in the airway, including chronic obstructive bronchitis and emphysema. It is most often caused by tobacco smoking, but can also be caused by other airborne irritants (such as coal dust) and occasionally by genetic abnormalities, such as α1-antitrypsin deficiency.

Antinuclear antibodies

(ANAs). Heterogeneous autoantibodies specific for one or more antigens present in the nucleus, including chromatin, nucleosomes and ribonuclear proteins. ANAs are found in association with many different autoimmune diseases.

K/BxN transgenic mouse

A mouse strain formed by crossing NOD/Lt mice with C57BL/6 KRN T cell receptor-transgenic mice in which T cells recognize a peptide from the autoantigen glucose-6-phosphate isomerase (GPI). These mice develop a form of arthritis that is mediated, and can be transferred, by circulating antibody specific for GPI.

Immunoediting

The process by which interaction of a heterogeneous population of tumour cells with the immune system generates tumour variants with reduced immunogenicity that might therefore escape from immune responses.

Angiogenesis

The development of new blood vessels from existing blood vessels. Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in granulation tissue formation. It is also a fundamental step for the growth of dormant tumours.

Myeloid-derived suppressor cells

A heterogenous collection of cells at different stages in the myeloid and monocytic differentiation pathway that have immunosuppressive functions. These cells include bona fide monocytes and neutrophils.

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Mantovani, A., Cassatella, M., Costantini, C. et al. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11, 519–531 (2011). https://doi.org/10.1038/nri3024

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