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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.* ; Stark, K.*

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

JCI insight 6:e150862 (2021)
Publ. Version/Full Text DOI
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Covid-19 ; Cytokines ; Neutrophils ; Proteomics ; Vascular Biology; Converting Enzyme; Spike Protein; Lung Injury; P-selectin; Activation; Inhibition; Receptor; Cxcr1; Ace2; Thrombosis
ISSN (print) / ISBN 2379-3708
e-ISSN 2379-3708
Journal JCI insight
Quellenangaben Volume: 6, Issue: 18, Pages: , Article Number: e150862 Supplement: ,
Publisher Clarivate
Publishing Place Ann Arbor, Michigan
Reviewing status Peer reviewed
Grants Federal Ministry of Education and Research (BMBF)
Deutsche Forschungsgemeinschaft (DFG)
DFG
DFG Clinician Scientist Programme PRIME
DZHK
European Research Council under the European Union Horizon 2020 research and innovation progamme
German Ministry of Education and Research (BMBF), as part of the National Research Node "Mass spectrometry in Systems Medicine" (MSCoresys)
COMBAT C19IR study group
Deutsche Herzstiftung e.V