Targeting potential drivers of COVID-19: Neutrophil extracellular traps

Barnes, Betsy J.; Adrover, Jose M.; Baxter-Stoltzfus, Amelia; Borczuk, Alain; Cools-Lartigue, Jonathan; Crawford, James M.; Daßler-Plenker, Juliane; Guerci, Philippe; Huynh, Caroline; Knight, Jason S.; Loda, Massimo; Looney, Mark R.; McAllister, Florencia; Rayes, Roni; Renaud, Stephane; Rousseau, Simon; Salvatore, Steven; Schwartz, Robert E.; Spicer, Jonathan D.; Yost, Christian C.; Weber, Andrew; Zuo, Yu; Egeblad, Mikala

and phagocytosis (Schönrich and Raftery, 2016) . However, neutrophils have another much less recognized means of killing pathogens: the formation of NETs (Brinkmann et al., 2004) . NETs are web-like structures of DNA and proteins expelled from the neutrophil that ensnare pathogens (Fig. 2) . Expelling DNA to the extracellular space is not widely recognized as a critical immune function. Yet, even plants have specialized cells that kill soil pathogens by this mechanism (Wen et al., 2009) . NET formation is a regulated process, although the signals involved are incompletely understood. Key enzymes in the formation of NETs are: neutrophil elastase (NE), which degrades intracellular proteins and triggers nuclear disintegration; peptidyl arginine deiminase type 4 (PAD4), which citrullinates histones to facilitate the decondensation and release of the chromosomal DNA; and gasdermin D, which generates pores in the membrane of the neutrophil, thereby facilitating cell membrane rupture and the expulsion of DNA and the associated molecules Kaplan and Radic, 2012; Papayannopoulos, 2018; Papayannopoulos et al., 2010; Rohrbach et al., 2012; Sollberger et al., 2018) . Although NETs are beneficial in the host defense against pathogens, collateral damage from sustained NET formation also stimulates many disease processes, including those that occur during viral infections (Schönrich and Raftery, 2016) . Indeed, excessive NET formation can trigger a cascade of inflammatory reactions that promotes cancer cell metastasis, destroys surrounding tissues, facilitates microthrombosis, and results in permanent organ damage to the pulmonary, cardiovascular, and renal systems (Jorch and Kubes, 2017; Kessenbrock et al., 2009; Papayannopoulos, 2018; Fig. 3) . Importantly, these are three commonly affected organ systems in severe COVID-19 (Bonow et al., 2020; Chen et al., 2020b) .