Usage Information
Citation Information: JCI Insight. 2021;6(18):e150862. https://doi.org/10.1172/jci.insight.150862.
Abstract
Neutrophils provide a critical line of defense in immune responses to various pathogens, inflicting self-damage upon transition to a hyperactivated, procoagulant state. Recent work has highlighted proinflammatory neutrophil phenotypes contributing to lung injury and acute respiratory distress syndrome (ARDS) in patients with coronavirus disease 2019 (COVID-19). Here, we use state-of-the art mass spectrometry–based proteomics and transcriptomic and correlative analyses as well as functional in vitro and in vivo studies to dissect how neutrophils contribute to the progression to severe COVID-19. We identify a reinforcing loop of both systemic and neutrophil intrinsic IL-8 (CXCL8/IL-8) dysregulation, which initiates and perpetuates neutrophil-driven immunopathology. This positive feedback loop of systemic and neutrophil autocrine IL-8 production leads to an activated, prothrombotic neutrophil phenotype characterized by degranulation and neutrophil extracellular trap (NET) formation. In severe COVID-19, neutrophils directly initiate the coagulation and complement cascade, highlighting a link to the immunothrombotic state observed in these patients. Targeting the IL-8–CXCR-1/-2 axis interferes with this vicious cycle and attenuates neutrophil activation, degranulation, NETosis, and IL-8 release. Finally, we show that blocking IL-8–like signaling reduces severe acute respiratory distress syndrome of coronavirus 2 (SARS-CoV-2) spike protein–induced, human ACE2–dependent pulmonary microthrombosis in mice. In summary, our data provide comprehensive insights into the activation mechanisms of neutrophils in COVID-19 and uncover a self-sustaining neutrophil–IL-8 axis as a promising therapeutic target in severe SARS-CoV-2 infection.
Authors
Rainer Kaiser, Alexander Leunig, Kami Pekayvaz, Oliver Popp, Markus Joppich, Vivien Polewka, Raphael Escaig, Afra Anjum, Marie-Louise Hoffknecht, Christoph Gold, Sophia Brambs, Anouk Engel, Sven Stockhausen, Viktoria Knottenberg, Anna Titova, Mohamed Haji, Clemens Scherer, Maximilian Muenchhoff, Johannes C. Hellmuth, Kathrin Saar, Benjamin Schubert, Anne Hilgendorff, Christian Schulz, Stefan Kääb, Ralf Zimmer, Norbert Hübner, Steffen Massberg, Philipp Mertins, Leo Nicolai, Konstantin Stark
Usage data is cumulative from September 2022 through September 2023.
| Usage | JCI | PMC |
|---|---|---|
| Text version | 1,435 | 388 |
| 127 | 162 | |
| Figure | 317 | 4 |
| Supplemental data | 72 | 10 |
| Citation downloads | 31 | 0 |
| Totals | 1,982 | 564 |
| Total Views | 2,546 | |
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.
