IL-1 Mediates Tissue-Specific Inflammation and Severe Respiratory Failure in COVID-19

  1. Georgios Renieris
  2. Eleni Karakike
  3. Theologia Gkavogianni
  4. Dionysia-Eirini Droggiti
  5. Emmanouil Stylianakis
  6. Theano Andriopoulou
  7. Victoria-Marina Spanou
  8. Dionyssios Kafousopoulos
  9. Mihai G. Netea
  10. Jesper Eugen-Olsen
  11. John Simard
  12. Evangelos J. Giamarellos-Bourboulis

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Abstract

Acute respiratory distress syndrome (ARDS) in COVID-19 has been associated with catastrophic inflammation. We present measurements in humans and a new animal model implicating a role in danger-associated molecular patterns. Calprotectin (S100A8/A9) and high-mobility group box 1 (HMGB1) were measured in patients without/with ARDS, and admission calprotectin was associated with soluble urokinase plasminogen activator receptor (suPAR). An animal model was developed by intravenous injection of plasma from healthy or patients with COVID-19 ARDS into C57/BL6 mice once daily for 3 consecutive days. Mice were treated with one anti-S100A8/A9 antibody, the IL-1 receptor antagonist anakinra or vehicle, and Flo1-2a anti-murine anti-IL-1α monoclonal antibody or the specific antihuman IL-1α antibody XB2001 or isotype controls. Cytokines and myeloperoxidase (MPO) were measured in tissues. Calprotectin, but not HMGB1, was elevated in ARDS. Higher suPAR indicated higher calprotectin. Animal challenge with COVID-19 plasma led to inflammatory reactions in murine lung and intestines as evidenced by increased levels of TNFα, IL-6, IFNγ, and MPO. Lung inflammation was attenuated with anti-S100A8/A9 pre-treatment. Anakinra treatment restored these levels. Similar decrease was found in mice treated with Flo1-2a but not with XB2001. Circulating alarmins, specifically calprotectin, of critically ill COVID-19 patients induces tissue-specific inflammatory responses through an IL-1-mediated mechanism. This could be attenuated through inhibition of IL-1 receptor or of IL-1α.

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  1. Version published to 10.1159/000524560
  2. ScreenIT

    SciScore for 10.1101/2021.04.09.21255190: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: Clinical study: Plasma samples from a cohort of 60 patients with and without ARDS that was determined to be caused by SARS-CoV (approval 30/20 by the National Ethics Committee of Greece; approval IS 021-20 by the National Organization for Medicines of Greece) and from 40 participants in the SAVE trial (suPAR-guided Anakinra treatment for Validation of the risk and Early management of severe respiratory failure by COVID-19; EudraCT number 2020-001466-11; National Ethics Committee approval 38/20; National Organization for Medicines approval ISO 28/20;
    Consent: Patients were enrolled after written informed consent was provided by themselves or by first-degree relatives in case of patients unable to consent.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableWe studied 80 male and female C57Bl6 mice (7-8 weeks old).

    Table 2: Resources

    Antibodies
    SentencesResources
    ) anti-murine IL-1α antibody Flo1-2a or human IL-1α antibody XB2001, or murine isotype control (XBiotech, TX, USA).
    ) anti-murine IL-1α
    suggested: None
    anti-murine
    suggested: None
    human IL-1α
    suggested: (Miltenyi Biotec Cat# 130-109-304, RRID:AB_2652396)
    Experimental Models: Organisms/Strains
    SentencesResources
    We studied 80 male and female C57Bl6 mice (7-8 weeks old).
    C57Bl6
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04357366RecruitingsuPAR-guided Anakinra Treatment for Validation of the Risk a…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  3. Version published to 10.1101/2021.04.09.21255190v2 on medRxiv
  4. Version published to 10.1101/2021.04.09.21255190v1 on medRxiv