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

Authors :
Rainer Kaiser
Alexander Leunig
Kami Pekayvaz
Oliver Popp
Markus Joppich
Vivien Polewka
Raphael Escaig
Afra Anjum
Marie-Louise Hoffknecht
Christoph Gold
Sophia Brambs
Anouk Engel
Sven Stockhausen
Viktoria Knottenberg
Anna Titova
Mohamed Haji
Clemens Scherer
Maximilian Muenchhoff
Johannes C. Hellmuth
Kathrin Saar
Benjamin Schubert
Anne Hilgendorff
Christian Schulz
Stefan Kääb
Ralf Zimmer
Norbert Hübner
Steffen Massberg
Philipp Mertins
Leo Nicolai
Konstantin Stark
Source :
JCI Insight, Vol 6, Iss 18 (2021)
Publication Year :
2021
Publisher :
American Society for Clinical investigation, 2021.

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 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 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.

Subjects

Subjects :
COVID-19
Vascular biology
Medicine

Details

Language :
English
ISSN :
23793708
Volume :
6
Issue :
18
Database :
Directory of Open Access Journals
Journal :
JCI Insight
Publication Type :
Academic Journal
Accession number :
edsdoj.6c76effe0be0417985fb0f08c49e4b8c
Document Type :
article
Full Text :
https://doi.org/10.1172/jci.insight.150862