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

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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. and Leunig, A. and Pekayvaz, K. and Popp, O. and Joppich, M. and Polewka, V. and Escaig, R. and Anjum, A. and Hoffknecht, M.L. and Gold, C. and Brambs, S. and Engel, A. and Stockhausen, S. and Knottenberg, V. and Titova, A. and Haji, M. and Scherer, C. and Muenchhoff, M. and Hellmuth, J.C. and Saar, K. and Schubert, B. and Hilgendorff, A. and Schulz, C. and Kääb, S. and Zimmer, R. and Hübner, N. and Massberg, S. and Mertins, P. and 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
Publisher:American Society for Clinical Investigation
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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