Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19

Kaiser, Rainer; Leunig, Alexander; Pekayvaz, Kami; Popp, Oliver; Joppich, Markus; Polewka, Vivien; Escaig, Raphael; Anjum, Afra; Hoffknecht, Marie-Louise; Gold, Christoph; Brambs, Sophia; Engel, Anouk; Stockhausen, Sven; Knottenberg, Viktoria; Titova, Anna; Haji, Mohamed; Scherer, Clemens; Muenchhoff, Maximilian; Hellmuth, Johannes C.; Saar, Kathrin; Schubert, Benjamin; Hilgendorff, Anne; Schulz, Christian; Kaeaeb, Stefan; Zimmer, Ralf; Huebner, Norbert; Massberg, Steffen; Mertins, Philipp; Nicolai, Leo und Stark, Konstantin (2021): Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19. In: Jci Insight, Bd. 6, Nr. 18, e150862

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 neutrophildriven 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch