Increased Autotaxin Levels in Severe COVID-19, Correlating with IL-6 Levels, Endothelial Dysfunction Biomarkers, and Impaired Functions of Dendritic Cells

  1. Ioanna Nikitopoulou
  2. Dionysios Fanidis
  3. Konstantinos Ntatsoulis
  4. Panagiotis Moulos
  5. George Mpekoulis
  6. Maria Evangelidou
  7. Alice G. Vassiliou
  8. Vasiliki Dimakopoulou
  9. Edison Jahaj
  10. Stamatios Tsipilis
  11. Stylianos E. Orfanos
  12. Ioanna Dimopoulou
  13. Emmanouil Angelakis
  14. Karolina Akinosoglou
  15. Niki Vassilaki
  16. Argyrios Tzouvelekis
  17. Anastasia Kotanidou
  18. Vassilis Aidinis

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Abstract

Autotaxin (ATX; ENPP2) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling phospholipid. Genetic and pharmacologic studies have previously established a pathologic role for ATX and LPA signaling in pulmonary injury, inflammation, and fibrosis. Here, increased ENPP2 mRNA levels were detected in immune cells from nasopharyngeal swab samples of COVID-19 patients, and increased ATX serum levels were found in severe COVID-19 patients. ATX serum levels correlated with the corresponding increased serum levels of IL-6 and endothelial damage biomarkers, suggesting an interplay of the ATX/LPA axis with hyperinflammation and the associated vascular dysfunction in COVID-19. Accordingly, dexamethasone (Dex) treatment of mechanically ventilated patients reduced ATX levels, as shown in two independent cohorts, indicating that the therapeutic benefits of Dex include the suppression of ATX. Moreover, large scale analysis of multiple single cell RNA sequencing datasets revealed the expression landscape of ENPP2 in COVID-19 and further suggested a role for ATX in the homeostasis of dendritic cells, which exhibit both numerical and functional deficits in COVID-19. Therefore, ATX has likely a multifunctional role in COVID-19 pathogenesis, suggesting that its pharmacological targeting might represent an additional therapeutic option, both during and after hospitalization.

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  1. Version published to 10.3390/ijms221810006
  2. ScreenIT

    SciScore for 10.1101/2021.07.30.21261361: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: All collected data were anonymized in standardized forms and informed consent was obtained from all individuals or patients’ next-of-kin for severe cases.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    BlindingMeasurements were performed in a blinded fashion in triplicates using the Triturus automated analyser (Grifols, Barcelona, Spain).
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Bulk/ single cell RNA-seq data analysis and mining: The available single cell RNA-seq object was mined for each one of the datasets (Table 1) using Seurat package v3 (28).
    Seurat
    suggested: (SEURAT, RRID:SCR_007322)
    More specifically, reads where EDASeq normalized, filtered using default parameters and then PANDORA algorithm was used to combine results of DESeq (32), DESeq2 (33), limma-voom (34),
    DESeq
    suggested: (DESeq, RRID:SCR_000154)
    DESeq2
    suggested: (DESeq, RRID:SCR_000154)
    , edgeR (35) and ABSSeq (36) methods.
    edgeR
    suggested: (edgeR, RRID:SCR_012802)
    Statistical analysis: Statistical significance was assessed with the Prism (GraphPad) software with the appropriate test according to the distribution of values and their complexity, as detailed in each figure legend.
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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: 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: 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.

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

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  3. Version published to 10.1101/2021.07.30.21261361v1 on medRxiv