Increased Autotaxin Levels in Severe COVID-19, Correlating with IL-6 Levels, Endothelial Dysfunction Biomarkers, and Impaired Functions of Dendritic Cells.
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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D000328:Adult D000368:Aged D000369:Aged, 80 and over D015415:Biomarkers D000086382:COVID-19 D015331:Cohort Studies D066264:Datasets as Topic D003713:Dendritic Cells D003907:Dexamethasone D004730:Endothelium, Vascular D005260:Female D006801:Humans D015850:Interleukin-6 D008297:Male D008875:Middle Aged D010726:Phosphodiesterase Inhibitors D010727:Phosphoric Diester Hydrolases D000081246:RNA-Seq D012121:Respiration, Artificial D000086402:SARS-CoV-2 D012720:Severity of Illness Index D015398:Signal Transduction D059010:Single-Cell Analysis
COVID-19 autotaxin (ATX ENPP2) lysophosphatidic acid (LPA) vascular dysfunction ARDS cytokine storm dendritic cells (DCs) pulmonary fibrosis