Inhibiting Neutrophil Extracellular Traps (NETs) in Immune Injury and Pathologic Clotting

Graphic- Inhibiting Neutrophil Extracellular Traps (NETs) in Immune Injury and Pathologic Clotting
Neonatal NET-inhibitory Factor (nNIF) blocks the neutrophil extracellular trap (NET) formation and pathologic clotting associated with pneumonia in patients with COVID-19.

Deficient or excess immune system activities cause many human diseases.  To understand the mechanisms of immune injury and their links to pathologic clotting, University of Utah Health investigators Christian Yost, MD, Guy Zimmerman, MD, and colleagues defined features of neutrophil extracellular traps (NETs). NETs are extracellular lattices of sticky, unwound DNA studded with antimicrobial proteins which are normally released by neutrophils to capture and kill microbes. However, excess NET formation leads to inflammatory injury and clotting in diseases such as sepsis. These researchers also discovered a protein, produced by the placenta, which blocks NET formation. Called neonatal NET-Inhibitory Factor (nNIF), this protein was shown in mouse studies to improve survival of severe infection.

Yost and Zimmerman’s work allowed fellow University of Utah Health investigator Elizabeth Middleton, MD, to respond immediately when COVID-19 struck. Middleton and colleagues identified a connection between NET-related clotting and pneumonia and respiratory failure in patients with COVID-19. They also found that nNIF blocked NET formation in COVID-19 patients’ blood. Thus, by triggering pathological clotting, NET formation may contribute to serious symptoms of severe COVID-19. This discovery highlights NET inhibition as a promising strategy for new therapies.


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Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation. Yost CC, Schwertz H, Cody MJ, Wallace JA, Campbell RA, Vieira-de-Abreu A, Araujo CV, Schubert S, Harris ES, Rowley JW, Rondina MT, Fulcher JM, Koening CL, Weyrich AS, Zimmerman GA. J Clin Invest. 2016 Oct 3;126(10):3783-3798.

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Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Middleton EA, He XY, Denorme F, Campbell RA, Ng D, Salvatore SP, Mostyka M, Baxter-Stoltzfus A, Borczuk AC, Loda M, Cody MJ, Manne BK, Portier I, Harris ES, Petrey AC, Beswick EJ, Caulin AF, Iovino A, Abegglen LM, Weyrich AS, Rondina MT, Egeblad M, Schiffman JD, Yost CC. Blood. 2020 Sep 3;136(10):1169-1179.