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

Severe COVID-19 is associated with a cytokine storm characterized by increased plasma concentrations of IL1β, IL2, IL6, IL7, IL8, IL10, IL17, IFNγ, IFNγ-inducible protein 10, monocyte chemoattractant protein 1 (MCP1), G-CSF, macrophage inflammatory protein 1α, and TNFα Mehta et al., 2020; Ruan et al., 2020; Wu and Yang, 2020; Zhang et al., 2020) . These inflammatory mediators regulate neutrophil activity and induce the expression of chemoattractants (molecules that increase the trafficking of neutrophils to sites of inflammation). Moreover, cytokine storms lead to acute lung injury, ARDS, and death (Channappanavar and Perlman, 2017; Chousterman et al., 2017) . It is especially noteworthy that NETs can induce macrophages to secrete IL1β and that IL1β enhances NET formation in various diseases, including aortic aneurysms and atherosclerosis (Kahlenberg et al., 2013; Meher et al., 2018; Sil et al., 2017; Warnatsch et al., 2015) . Together, these data suggest that under conditions in which the normal signals to dampen inflammation are lost, such as during a cytokine storm, a signaling loop between macrophages and neutrophils can lead to uncontrollable, progressive inflammation. Indeed, a correlation between NETs and IL1β exists in severe asthma (Lachowicz-Scroggins et al., 2019) . If a NET-IL1β loop is activated in severe COVID-19, the accelerated production of NETs and IL1β could accelerate respiratory decompensation, the formation of microthrombi, and aberrant immune responses. Importantly, IL1β induces IL6 (Dinarello, 2009) , and IL6 has emerged as a promising target for COVID-19 treatment (Mehta et al., 2020; Xu et al., 2020 Preprint) . IL6 can signal via classic and trans-signaling (Calabrese and Rose-John, 2014) . In classic signaling, IL6 binds to a complex of the transmembrane receptor IL6Rα with the common cytokine receptor gp130. In trans-signaling, soluble IL6Rα (sIL6Rα) binds IL6 to initiate signaling via gp130. Trans-signaling is strongly associated with pro-inflammatory states (Calabrese and Rose-John, 2014) , and lower levels of sIL6Rα are associated with better lung function in, e.g., asthma (Ferreira et al., 2013; Hawkins et al., 2012) . Neutrophils can shed sIL6Rα in response to IL8 (Marin et al., 2002) , which is abundant in the COVID-19-associated cytokine storm (Wu and Yang, 2020; Zhang et al., 2020) . Together, these findings lead us to speculate that antagonizing IL-6 trans-signaling and/or IL1β could be effective indirect strategies for targeting neutrophils and NETs in severe COVID-19.