Dysregulation in the formation and/or clearance of neutrophil extracellular traps (NETs) is important in immune dysregulation and organ damage in chronic inflammatory conditions. Studies in 2019 have shown how certain genetic susceptibilities to autoimmunity can promote NET-mediated inflammation, and expanded the role for NETs in vascular damage and premature atherosclerosis.
Key advances
Genetic risk alleles for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are functionally linked to increased peptidylarginine deiminase 4 expression and enhanced neutrophil extracellular trap (NET) formation2.
Insights into the monogenic autoinflammatory disease deficiency of adenosine deiminase 2 (DADA2) link adenosine metabolism with neutrophil activation, NET formation and pathogenic inflammatory cascades3.
Histone H4, which is present in NETs, is involved in plaque destabilization in atherosclerosis, an important co-morbidity of RA and SLE4.
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References
Gupta, S. & Kaplan, M. J. The role of neutrophils and NETosis in autoimmune and renal diseases. Nat. Rev. Nephrol. 12, 402–413 (2016).
Odqvist, L. et al. Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus. Ann. Rheum. Dis. 78, 1363–1370 (2019).
Carmona-Rivera, C. et al. Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2. Blood 134, 395–406 (2019).
Silvestre-Roig, C. et al. Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death. Nature 569, 236–240 (2019).
Wang, Y. et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J. Cell Biol. 184, 205–213 (2009).
Suzuki, A. et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat. Genet. 34, 395–402 (2003).
Chang, H. H. et al. The W620 polymorphism in PTPN22 disrupts its interaction with peptidylarginine deiminase type 4 and enhances citrullination and NETosis. Arthritis Rheumatol. 67, 2323–2334 (2015).
Zhou, Q. et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N. Engl. J. Med. 370, 911–920 (2014).
Ali, A. A. et al. Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome. Nat. Commun. 10, 1916 (2019).
Knight, J. S. et al. Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis. Circ. Res. 114, 947–956 (2014).
Acknowledgements
The work of the authors is supported financially by the Intramural Research Program at the US National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (to M.J.K.) and by the Swedish Research Council (to G.W.).
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Wigerblad, G., Kaplan, M.J. NETs spread ever wider in rheumatic diseases. Nat Rev Rheumatol 16, 73–74 (2020). https://doi.org/10.1038/s41584-019-0352-1
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DOI: https://doi.org/10.1038/s41584-019-0352-1
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