Targeting the chemokine receptor CXCR4 with histamine analogue to reduce inflammation in juvenile arthritis: a proof of concept for COVID-19 therapeutic approach

  1. Nassima Bekaddour
  2. Nikaïa Smith
  3. Benoit Beitz
  4. Alba Llibre
  5. Tom Dott
  6. Anne Baudry
  7. Anne-Sophie Korganow
  8. Sébastien Nisole
  9. Richard Mouy
  10. Sylvain Breton
  11. Brigitte Bader-Meunier
  12. Darragh Duffy
  13. Benjamin Terrier
  14. Benoit Schneider
  15. Pierre Quartier
  16. Mathieu P Rodero
  17. Jean-Philippe Herbeuval

Reviewed by

Read the full article See related articles

Discuss this preprint

Start a discussion What are Sciety discussions?

Listed in

Log in to save this article

Abstract

Among immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies. The uncontrolled activation of monocytes and the subsequent excessive production of inflammatory factors damage bone-cartilage joints in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. Inflammatory monocytes also exert a critical role in the cytokine storm induced by SARS-CoV2 infection in severe COVID-19 patients. The moderate beneficial effect of current therapies and clinical trials highlights the need of alternative strategies targeting monocytes to treat RA and COVID-19 pathologies. Here, we show that targeting CXCR4 with small amino compound such as the histamine analogue clobenpropit (CB) inhibits spontaneous and induced-production of a set of key inflammatory cytokines by monocytes isolated from blood and synovial fluids of JIA patients. Moreover, daily intraperitoneal CB treatment of arthritic mice results in significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption leading to reduction of disease progression. Finally, we provide the prime evidence that the exposure of whole blood from hospitalized COVID-19 patients to CB significantly reduces levels of key cytokine-storm-associated factors including TNF-α, IL-6 and IL-1β. These overall data show that targeting CXCR4 with CB-like molecules may represent a promising therapeutic option for chronic and viral-induced inflammatory diseases.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2021.10.24.465080: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Experimental procedures with human blood were done according to the European Union guidelines and the Declaration of Helsinki and informed consent was obtained from all donors (healthy and patients).
    Field Sample Permit: Biological collection and informed consent were approved by the Direction de la Recherche Clinique et Innovation (DRCI) and the French Ministry of Research (N°2019-3677).
    IRB: The study conforms to the principles outlined in the Declaration of Helsinki and received approval by the appropriate Institutional Review Board (Cochin-Port Royal Hospital, Paris
    IACUC: The WBI Animal Care and Use Committee reviewed and approved all mouse experiments (IACUC NO. 17-006).
    Euthanasia Agents: The mice were anesthetized and exsanguinated into pre-chilled EDTA tubes.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    BlindingMice: Animal experiments were performed blindly by Washington Biotechnology, INC.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    After fixation, cells were incubated in Perm-S solution containing the anti-cytokine antibodies and isotopes Ir for 30 min at RT (Maxpar Perm-S buffer;Fluidigm).
    anti-cytokine
    suggested: None
    Briefly, the cells were fixed for 20 min at RT with 250 μL of the Inside Fix solution then washed and stained in 100 μL of the Inside Perm solution containing PE anti-TNF (clone cA2, Miltenyi Biotec) and APC anti-IL-1β (clone REA1172, Miltenyi Biotec) antibody at 1/50 for 30 min at room temperature.
    anti-TNF
    suggested: None
    anti-IL-1β
    suggested: None
    Simoa digital ELISA specific for TNF-α was developed using a Quanterix Homebrew Assay and two commercially available antibodies[38].
    antibodies[38
    suggested: None
    Software and Algorithms
    SentencesResources
    Data were acquired using a CyTOF2 instrument (Fluidigm) and analyzed using both FlowJo software for cleaning data and the viSNE algorithm in Cytobank to perform main analysis.
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Cytobank
    suggested: (Cytobank, RRID:SCR_014043)
    Pathway analysis was performed using DAVID bioinformatics databank (https://david.ncifcrf.gov).
    DAVID
    suggested: (DAVID, RRID:SCR_001881)

    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: We detected the following sentences addressing limitations in the study:
    To overcome these limitations, novel strategies such as Janus kinases (JAK) inhibitors, which are small molecules inhibiting the activity of JAK, showed reasonable success in adult form of arthritis[30][31][32]. As for strategies targeting JAK, we demonstrate that CB treatment exhibits wide-ranging cytokine inhibition in vitro, ex vivo and in vivo. CB acts, however, one step upstream of JAK inhibitors, by blocking the production of inflammatory cytokines rather than blocking cytokine-mediated signaling, which may confer some advantages in terms of therapies efficacies. This is in fact supported by the strong inhibition of disease progression in CB-treated RA mice, validating the concept of targeting CXCR4 with CB-like molecules to treat arthritic diseases. CB indeed holds all the required hallmarks for a promising new drug to treat RA: CB is a small molecule, which does not show any side effects in preclinical models in vivo, targets the widely expressed receptor CXCR4 on immune cells, and acts on cytokine production with a broad anti-inflammatory spectrum. To illustrate the potential benefit of CB in another inflammatory disease context, we studied samples from COVID-19 patients. Hypersecretion of inflammatory cytokines by monocytes and macrophages in lung seems to be central in COVID-19 pathology. Studies of SARS-CoV2 infection have revealed highly inflammatory monocyte/macrophage[9,10],[33] population in the bronchoalveolar lavage of patients with severe but not mild COVID...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

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

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 27. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.10.24.465080 on bioRxiv