Increased Autotaxin levels in severe COVID-19, correlating with IL-6 levels, endothelial dysfunction biomarkers, and impaired functions of dendritic cells

Nikitopoulou, I.; Fanidis, D.; Ntatsoulis, K.; Moulos, P.; Mpekoulis, G.; Evangelidou, M.; Dimakopoulou, V.; Vassiliou, A. G.; Jahaj, E.; Tsipilis, S.; Orfanos, S. E.; Dimopoulou, I.; Angelakis, E.; Akinosoglou, K.; Vassilaki, N.; Tzouvelekis, A.; Kotanidou, A.; Aidinis, V.

Autotaxin (ATX; ENPP2) is a secreted lysophospholipase D catalysing the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signalling phospholipid. Genetic and pharmacologic studies have previously established a pathologic role for ATX and LPA signalling 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 RNAseq datasets revealed the expression landscape of ENPP2 in COVID-19 and further suggested a role for ATX in the homeostasis of dendritic cells, that exhibit both numerical and functional deficits in COVID-19. Therefore, ATX has likely a multifunctional role in COVID-19 pathogenesis, worth of suggesting that its pharmacological targeting might represent an additional therapeutic option.