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

• Main Authors: Ioanna Nikitopoulou, Dionysios Fanidis, Konstantinos Ntatsoulis, Panagiotis Moulos, George Mpekoulis, Maria Evangelidou, Alice G. Vassiliou, Vasiliki Dimakopoulou, Edison Jahaj, Stamatios Tsipilis, Stylianos E. Orfanos, Ioanna Dimopoulou, Emmanouil Angelakis, Karolina Akinosoglou, Niki Vassilaki, Argyrios Tzouvelekis, Anastasia Kotanidou, Vassilis Aidinis
• Format: Article
• Language: English
• Published: MDPI AG 2021-09-01
• Series: International Journal of Molecular Sciences
• Subjects: COVID-19; ARDS; cytokine storm; vascular dysfunction; pulmonary fibrosis; autotaxin (ATX
• Online Access: https://www.mdpi.com/1422-0067/22/18/10006

Autotaxin (ATX; <i>ENPP2</i>) 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 <i>ENPP2</i> 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 <i>ENPP2</i> 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.