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


  • R. Kaiser
  • A. Leunig
  • K. Pekayvaz
  • O. Popp
  • M. Joppich
  • V. Polewka
  • R. Escaig
  • A. Anjum
  • M.L. Hoffknecht
  • C. Gold
  • S. Brambs
  • A. Engel
  • S. Stockhausen
  • V. Knottenberg
  • A. Titova
  • M. Haji
  • C. Scherer
  • M. Muenchhoff
  • J.C. Hellmuth
  • K. Saar
  • B. Schubert
  • A. Hilgendorff
  • C. Schulz
  • S. Kääb
  • R. Zimmer
  • N. Hübner
  • S. Massberg
  • P. Mertins
  • L. Nicolai
  • K. Stark


  • JCI Insight


  • JCI Insight 6 (18): e150862


  • Neutrophils provide a critical line of defense in immune responses to various pathogens, but also inflict 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 suffering from COVID-19. Here, we utilize state-of-the art mass spectrometry-based proteomics, 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 interleukin-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 SARS-CoV-2 spike protein-induced, hACE2-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 promising therapeutic target in severe SARS-CoV-2 infection.