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Targeting of the NLRP3 Inflammasome for early COVID-19

Carlo Marchetti, Kara Mould, Isak W. Tengesdal, William J Janssen, Charles A. Dinarello
doi: https://doi.org/10.1101/2021.02.24.432734
Carlo Marchetti
1Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA
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  • For correspondence: carlo.marchetti@cuanschutz.edu
Kara Mould
2National Jewish Health, 2930, Medicine, Denver, Colorado, United States
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Isak W. Tengesdal
1Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA
3Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Geert Grooteplein Zuid 8, 6525, GA, Nijmegen, The Netherlands
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William J Janssen
2National Jewish Health, 2930, Medicine, Denver, Colorado, United States
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Charles A. Dinarello
1Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA
3Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Geert Grooteplein Zuid 8, 6525, GA, Nijmegen, The Netherlands
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Abstract

Following entry and replication of Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) into ACE2 expressing cells, the infected cells undergo lysis releasing more virus but also cell contents. In the lung, constitutive cytokines such as IL-1α are released together with other cell contents. A cascade of inflammatory cytokines ensues, including chemokines and IL-1β, triggering both local as well as systemic inflammation. This cascade of inflammatory cytokines in patients with COVID-19 is termed “Cytokine Release Syndrome” (CRS), and is associated with poor outcomes and death. Many studies reveal that blocking IL-1 activities in COVID-19 patients reduces disease severity and deaths. Here we report highly significant circulating levels of IL-1β, IL-1 Receptor antagonist, IL-6, TNFα, IL-10 and soluble urokinase plasminogen activator receptor in COVID-19 patients with mild or no symptoms. We also report that in circulating myeloid cells from the same patients, there is increased expression of the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) early in the infection. We observed increased NLRP3 gene expression in myeloid cells correlated with IL-1β gene expression and also with elevated circulating IL-1β levels. We conclude that early in SARS-CoV-2 infection, NLRP3 activation takes place and initiates the CRS. Thus, NLRP3 is a target to reduce the organ damage of inflammatory cytokines of the CRS.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted February 24, 2021.
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Targeting of the NLRP3 Inflammasome for early COVID-19
Carlo Marchetti, Kara Mould, Isak W. Tengesdal, William J Janssen, Charles A. Dinarello
bioRxiv 2021.02.24.432734; doi: https://doi.org/10.1101/2021.02.24.432734
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Targeting of the NLRP3 Inflammasome for early COVID-19
Carlo Marchetti, Kara Mould, Isak W. Tengesdal, William J Janssen, Charles A. Dinarello
bioRxiv 2021.02.24.432734; doi: https://doi.org/10.1101/2021.02.24.432734

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