IL-1β and TNF drive endothelial dysfunction and coagulopathy in acute COVID-19
et al., bioRxiv, doi:10.64898/2026.03.21.713333, Mar 2026
In vitro and mouse study showing benefit with dexamethasone, adalimumab (anti-TNF), anakinra (IL-1R antagonist), and anti-IL-1β antibodies in preventing SARS-CoV-2-induced endothelial dysfunction and coagulopathy.
Mostafavi et al., 25 Mar 2026, Australia, preprint, 13 authors.
Contact: l.labzin@uq.edu.au.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
Abstract: bioRxiv preprint doi: https://doi.org/10.64898/2026.03.21.713333; this version posted March 25, 2026. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
1
IL-1β and TNF drive endothelial dysfunction and coagulopathy in acute COVID-19.
2
3
Helen Mostafavi1, Brittany Hill1,2, Christina Nalkurthi2, Stefanie M Bader3,4, Yanshan Zhu1,,
4
Alexander Yu1, Philip M. Hansbro2, Marcel Doerflinger3,4, Matt D. Johansen2, Kirsty R.
5
Short5,6, Keng Yih Chew5,*, Emma J Gordon1,*, Larisa I Labzin1,6,7*
6
7
1
8
4072, Australia.
9
2
Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, QLD
Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty
10
of Science, Sydney, NSW, Australia
11
3
12
Australia.
13
4
Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
14
5
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane,
15
QLD 4072, Australia.
16
6
17
QLD 4072, Australia
18
7
19
Behavioural Sciences, The University of Queensland, Brisbane, Australia.
The Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, VIC 3052,
Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane,
Centre for Cardiovascular Health and Research, Faculty of Health, Medicine and
20
21
*
22
Corresponding author. Email: l.labzin@uq.edu.au
23
These authors contributed equally.
bioRxiv preprint doi: https://doi.org/10.64898/2026.03.21.713333; this version posted March 25, 2026. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
24
Abstract
25
26
Vascular dysfunction and coagulopathy are hallmarks of severe COVID-19. How SARS-
27
CoV-2 infection drives endothelial dysfunction, despite the virus not infecting or replicating
28
in endothelial cells, remains controversial. Here, we used an in vitro co-culture model of the
29
human pulmonary epithelial-endothelial cell barrier to investigate which inflammatory
30
mediators drive endothelial dysfunction during SARS-CoV-2 infection. SARS-CoV-2
31
infection of primary human bronchial epithelial cells increased adjacent endothelial cell
32
expression of the leukocyte adhesion marker ICAM-1, disrupted endothelial VE-cadherin
33
junctions, promoted endothelial cell death, and promoted platelet adherence to gaps in the
34
endothelial monolayers. Dexamethasone treatment rescued these dysregulated endothelial
35
phenotypes in infected co-cultures, confirming that inflammatory signalling was the primary
36
driver of SARS-CoV-2-induced endothelial dysfunction. Specifically, epithelial-derived TNF
37
and IL-1β promoted endothelial dysfunction, as inhibition of TNF or IL-1R signalling
38
blocked SARS-CoV-2-induced endothelial dysfunction in co-cultures. SARS-CoV-2-infected
39
wild-type mice, but not TNF, IL-1β, or TNF/IL-1β− deficient mice, displayed increased
40
endothelial ICAM-1 expression, while an anti-IL-1β monoclonal antibody prevented SARS-
41
CoV-2-induced ICAM-1 expression and fibrin deposition in aged K18-ACE2 mice. Our data
42
indicate that TNF and IL-1β are the specific cytokines that drive multiple aspects of
43
endothelial dysfunction during acute SARS-CoV-2 infection, and that..
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:p>\n Vascular dysfunction and coagulopathy are hallmarks of severe COVID-19. How SARS-CoV-2 infection drives endothelial dysfunction, despite the virus not infecting or replicating in endothelial cells, remains controversial. Here, we used an\n <jats:italic>in vitro</jats:italic>\n co-culture model of the human pulmonary epithelial-endothelial cell barrier to investigate which inflammatory mediators drive endothelial dysfunction during SARS-CoV-2 infection. SARS-CoV-2 infection of primary human bronchial epithelial cells increased adjacent endothelial cell expression of the leukocyte adhesion marker ICAM-1, disrupted endothelial VE-cadherin junctions, promoted endothelial cell death, and promoted platelet adherence to gaps in the endothelial monolayers. Dexamethasone treatment rescued these dysregulated endothelial phenotypes in infected co-cultures, confirming that inflammatory signalling was the primary driver of SARS-CoV-2-induced endothelial dysfunction. Specifically, epithelial-derived TNF and IL-1β promoted endothelial dysfunction, as inhibition of TNF or IL-1R signalling blocked SARS-CoV-2-induced endothelial dysfunction in co-cultures. SARS-CoV-2-infected wild-type mice, but not TNF, IL-1β, or TNF/IL-1β− deficient mice, displayed increased endothelial ICAM-1 expression, while an anti-IL-1β monoclonal antibody prevented SARS-CoV-2-induced ICAM-1 expression and fibrin deposition in aged K18-ACE2 mice. Our data indicate that TNF and IL-1β are the specific cytokines that drive multiple aspects of endothelial dysfunction during acute SARS-CoV-2 infection, and that inhibiting their signalling pathways may provide therapeutic benefit in preventing vascular complications of COVID-19.\n </jats:p>",
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