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| Item Type: | Article |
|---|---|
| Title: | Self-sustaining interleukin-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19 |
| Creators Name: | Kaiser, R., Leunig, A., Pekayvaz, K., Popp, O., Joppich, M., Polewka, V., Escaig, R., Anjum, A., Hoffknecht, M.L., Gold, C., Brambs, S., Engel, A., Stockhausen, S., Knottenberg, V., Titova, A., Haji, M., Scherer, C., Muenchhoff, M., Hellmuth, J.C., Saar, K., Schubert, B., Hilgendorff, A., Schulz, C., Kääb, S., Zimmer, R., Hübner, N., Massberg, S., Mertins, P., Nicolai, L. and Stark, K. |
| Abstract: | 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. |
| Keywords: | COVID-19, Interleukin-8, Lung, Neutrophil Activation, Neutrophils, Phenotype, SARS-CoV-2, Thrombosis, Animals, Mice |
| Source: | JCI Insight |
| ISSN: | 2379-3708 |
| Publisher: | American Society for Clinical Investigation |
| Volume: | 6 |
| Number: | 18 |
| Page Range: | e150862 |
| Date: | 22 September 2021 |
| Official Publication: | https://doi.org/10.1172/jci.insight.150862 |
| PubMed: | View item in PubMed |
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