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Neutrophils as emerging therapeutic targets

Abstract

Neutrophils are the most abundant circulating leukocytes, being the first line of defence against bacterial and fungal infections. However, neutrophils also contribute to tissue damage during various autoimmune and inflammatory diseases, and play important roles in cancer progression. The intimate but complex involvement of neutrophils in various diseases makes them exciting targets for therapeutic intervention but also necessitates differentiation of beneficial responses from potentially detrimental side effects. A variety of approaches to therapeutically target neutrophils have emerged, including strategies to enhance, inhibit or restore neutrophil function, with several agents entering clinical trials. However, challenges and controversies in the field remain.

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Fig. 1: Overview of neutrophil development and function.
Fig. 2: Signal transduction by neutrophil activating cell surface receptors.
Fig. 3: Neutrophils in cancer.
Fig. 4: Targeting neutrophils in diseases.

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Acknowledgements

The authors apologize to the authors of numerous outstanding publications that had to be omitted due to space limitations. This work was supported by the Hungarian National Agency for Research, Development and Innovation (K-NVKP_16-1-2016-0152956, VEKOP-2.3.2-16-2016-00002 and KKP 129954 to A.M.), the European Union’s Horizon 2020 IMI2 programme (RTCure project; grant no. 777357 to A.M.) and the Deutsche Forschungsgemeinschaft (SFB 914 projects B01 and Z03, grant no. SP621/5-1 to M.S.).

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Correspondence to Tamás Németh or Attila Mócsai.

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M.S. is a scientific advisor for Dompé Farmaceutici S.p.A. The other authors declare no competing interests.

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Glossary

Neutrophil extracellular traps

(NETs). A web of chromatin and granule proteins that are expelled from neutrophils during a unique form of cell death called ‘NETosis’ . The biological role of NETs is still debated.

Respiratory burst

The phenomenon of increased O2 consumption on neutrophil activation. It is primarily due to a non-mitochondrial mechanism through the activity of the neutrophil NADPH oxidase NOX2.

Low-density granulocytes

A subset of circulating granulocytes with unusually low density that appear in the mononuclear fraction during density gradient separation of leukocytes. Low-density granulocytes are abundant in certain autoimmune diseases, such as systemic lupus erythematosus. Their origin and functional importance in disease pathogenesis are poorly understood.

Formyl peptide receptors

G protein-coupled receptors recognizing N-formylated peptides of bacterial or mitochondrial origin during bacterial infection or tissue damage, respectively.

Swarming

The phenomenon of massive focal accumulation of neutrophils at sites of infection or tissue injury. It is likely mediated by positive-feedback amplification of neutrophil recruitment signals.

NADPH oxidase

A member of a family of transmembrane enzyme complexes leading to the generation of superoxide (O2.–) radicals. They are involved in reactive oxygen species generation by neutrophils (through NOX2), as well as several other redox signalling processes.

Peptidylarginine deiminase

A member of a family of enzymes involved in the citrullination of proteins (that is, the conversion of arginine into citrulline residues). Besides a number of biological functions, citrullination is also thought to generate neoantigens during autoimmune diseases.

CARD9

An adapter protein linking immune receptors to nuclear factor-κB activation in myeloid cells during fungal infection and other inflammatory processes.

Tyrosine kinase SYK

An intracellular tyrosine kinase mediating immunoreceptor tyrosine-based activation motif (ITAM)-based signalling by B cell receptors, Fc receptors and certain C-type lectins. SYK has diverse roles in immunity and inflammation.

Janus kinase

(JAK). A member of a family of intracellular tyrosine kinases mediating signalling by most (but not all) cytokine receptors through activation of signal transducer and activator of transcription (STAT)-family transcription factors. The JAK family consists of JAK1, JAK2, JAK3 and TYK2.

MCL1

An antiapoptotic member of the BCL-2 family present in various immune cells and overexpressed in certain tumours. MCL1 blocks the intrinsic apoptotic programme of neutrophils, and therefore MCL1 deficiency leads to severe neutropenia.

Resolution of inflammation

An active process of restoring normal tissue structure and function after an acute inflammatory insult. Defective resolution is thought to lead to chronic inflammation.

Myeloid-derived suppressor cell

(MDSC). A diverse subset of myeloid cells that promote tumour development by suppressing antitumour immunity. MDSCs may phenotypically be similar to monocytes (monocytic MDSCs) or granulocytes (granulocytic or polymorphonuclear MDSCs).

Plasmacytoid dendritic cells

A unique circulating subset of dendritic cells capable of producing large amounts of type I interferons. Besides their role in antimicrobial host defence, they likely contribute to autoimmune diseases such as systemic lupus erythematosus.

Anti-citrullinated peptide autoantibodies

(ACPAs). Autoantibodies against various citrullinated autoantigens present in a subset of patients with rheumatoid arthritis. It is still unclear how ACPAs participate in the pathogenesis of rheumatoid arthritis.

IL-23–IL-17 axis

An immune signalling pathway whereby IL-23 leads to IL-17 production by T helper 17 cells. Besides its role in antimicrobial host defence, the IL-23–IL-17 axis also participates in the development of various autoimmune and inflammatory diseases, such as psoriasis, and serves as a regulator of granulopoiesis.

Tumour-associated neutrophils

Neutrophils accumulating within the tumour tissue as one of the dominant tumour-infiltrating immune cell types in certain tumours. Tumour-associated neutrophils may exert either antitumoural (N1) or pro-tumoural (N2) effects.

Premetastatic niches

Local environments in distant secondary organs that promote the engraftment and colonization by primary tumour cells, leading to metastasis formation. Preparation of premetastatic niches begins long before the actual translocation of primary tumour cells.

Trogocytosis

A process whereby immune cells extract membrane fragments and cytoplasm from target cells by mechanically tearing out parts of the target cell. Neutrophils use trogocytosis to kill cancer cells in a process called ‘trogoptosis’.

ANCA-associated vasculitis

(AAV). Small-vessel vasculitis co-occurring with circulating antibodies against neutrophil components (anti-neutrophil cytoplasmic antibodies (ANCAs)). It is generally believed that ANCAs and ANCA-mediated neutrophil activation play a pathogenetic role in AAV.

Gout flares

The acute exacerbation of gouty arthritis, characterized by massive inflammation caused by deposition of monosodium urate crystals. Neutrophils are believed to be involved in the inflammation process during gout flares.

Endoplasmic reticulum stress

The accumulation of misfolded or unfolded proteins in the endoplasmic reticulum, for example, during prion diseases or on mutations leading to folding defects. Endoplasmic reticulum stress triggers a process called ‘unfolded protein response’ and may lead to apoptosis of the cell.

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Németh, T., Sperandio, M. & Mócsai, A. Neutrophils as emerging therapeutic targets. Nat Rev Drug Discov 19, 253–275 (2020). https://doi.org/10.1038/s41573-019-0054-z

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  • DOI: https://doi.org/10.1038/s41573-019-0054-z

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