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

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.