A Sticky Business: New Insights Into Neutrophil Extracellular Traps (NETs) in Physiology and Disease

Neutrophils are the first leukocytes recruited to sites of infection or injury. A newly recognized component in their arsenal of responses is the release of nuclear DNA to generate neutrophil extracellular traps (NETs), which are web-like structures composed of decondensed chromatin coated with neutrophil nuclear, granule, and cytoplasmic proteins. Since first described in 2004 by investigators studying neutrophils activated in vitro, the regulation and clinical relevance of NETosis has attracted broad attention, yet many fundamental knowledge gaps remain. Mechanisms leading to NET formation are only partially understood, and include deimination of histones by peptidyl arginine deiminase 4 (PAD4). Released NETs can trap microbes and may contribute to host defense, but the importance of this function is controversial. NETs can also cause proinflammatory damage to host tissues, and the NETs themselves are highly proinflammatory and prothrombotic.

Dr. Christian Yost will provide an overview of NETosis and its proposed beneficial effects and adverse consequences. He will present recent studies of human neonates leading to discovery of a family of peptide inhibitors of NETosis. Investigation of the activities of these inhibitors is relevant to the inflammatory biology of neonates and adults, and may lead to new therapeutic strategies to harness NET formation.

Dr. Denisa Wagner will discuss the evidence supporting an important role of NETs in thrombosis and inflammation. Mice lacking PAD4 or mice treated with deoxyribonuclease (DNase) I are protected from venous thrombosis and aging-associated fibrosis, and develop smaller post-ischemic cardiac infarcts. Dr. Wagner will propose why PAD4 and NETs will be an interesting drug target in thrombotic and cardiovascular disease.