Abstract
Systemic autoimmune diseases are characterized by the failure of the immune system to differentiate self from non-self. These conditions are associated with significant morbidity and mortality, and they can affect many organs and systems, having significant clinical heterogeneity. Recent discoveries have highlighted that neutrophils, and in particular the neutrophil extracellular traps that they can release upon activation, can have central roles in the initiation and perpetuation of systemic autoimmune disorders and orchestrate complex inflammatory responses that lead to organ damage. Dysregulation of neutrophil cell death can lead to the modification of autoantigens and their presentation to the adaptive immune system. Furthermore, subsets of neutrophils that seem to be more prevalent in patients with systemic autoimmune disorders can promote vascular damage and increased oxidative stress. With the emergence of new technologies allowing for improved assessments of neutrophils, the complexity of neutrophil biology and its dysregulation is now starting to be understood. In this Review, we provide an overview of the roles of neutrophils in systemic autoimmune and autoinflammatory diseases and address putative therapeutic targets that may be explored based on this new knowledge.
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Acknowledgements
G.W. and M.J.K. are supported by the intramural research program at NIAMS (ZIAAR041199).
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NIAMS has collaborative research agreements with Pfizer, Bristol Myers Squibb and Astra Zeneca. M.J.K. is on the Scientific Advisory Board of Citryll and Neutrolis. G.W. declares no competing interests.
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Glossary
- Neutrophil extracellular traps
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(NETs). Networks of extracellular DNA fibres containing granule proteins, such as myeloperoxidase and neutrophil elastase, that are formed by neutrophils as part of an active process.
- NADPH oxidase
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Membrane-bound enzymatic complex that catalyses the production of superoxide free radicals (a type of reactive oxygen species), which are used by neutrophils to kill microorganisms. This reaction is also known as the respiratory burst.
- Citrullination
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A post-translational modification of proteins that changes the amino acid arginine into a citrulline through deimination.
- Carbamylation
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A post-translational modification of proteins that attaches isocyanic acid to arginine, forming homocitrulline.
- cGAS–STING pathway
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An innate immune pathway that senses double-stranded DNA and activates a cellular response, often involving type I interferons.
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Wigerblad, G., Kaplan, M.J. Neutrophil extracellular traps in systemic autoimmune and autoinflammatory diseases. Nat Rev Immunol 23, 274–288 (2023). https://doi.org/10.1038/s41577-022-00787-0
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DOI: https://doi.org/10.1038/s41577-022-00787-0
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