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

Ioanna Nikitopoulou,Emmanouil Angelakis,Vassilis Aidinis,Maria Evangelidou,George Mpekoulis,Argyrios Tzouvelekis,Karolina Akinosoglou,Anastasia Kotanidou,Stylianos E Orfanos,Niki Vassilaki,Dionysios Fanidis,Konstantinos Ntatsoulis,Panagiotis Moulos,Vasiliki Dimakopoulou,Ioanna Dimopoulou,Stamatios Tsipilis,Alice G Vassiliou,Edison Jahaj

doi:10.3390/ijms221810006

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.

Highlights

The leading symptom of COVID-19, beyond cough and fever, is hypoxemia, leading to dyspnea in severe cases, attributed to impaired lung mechanics and/or vasoconstriction [1,2]
A significant increase was found in ENPP2 mRNA expression in mild and severe COVID-19 patients, as compared to non-infected subjects (Figure 1)
As shown here, increased ENPP2 mRNA expression was detected in nasopharyngeal swab samples from COVID-19 patients in comparison to non-infected healthy controls (Figure 1), while scRNAseq re-analysis revealed that the highest ENPP2 expressing cells in swabs are immune cells (Figures 5A and S5A), suggesting that CoV-2 infection stimulates ENPP2 expression from immune cells in the nasopharynx

Summary

Introduction

The leading symptom of COVID-19, beyond cough and fever, is hypoxemia, leading to dyspnea in severe cases, attributed to impaired lung mechanics and/or vasoconstriction [1,2]. Many discharged COVID-19 patients present with abnormally pulmonary architecture and functions [8,9,10,11,12], suggesting persisting fibrotic abnormalities, pending long-term follow up studies. Single-cell RNA sequencing (scRNAseq) analysis and transcriptional profiling indicated similarities in expression profiles between idiopathic pulmonary fibrosis (IPF) and COVID-19 [13,14], while CoV-2 infection has been suggested to stimulate the expression of major pro-fibrotic factors including TGFβ [15]. Patients with interstitial lung diseases (ILD) had an increased risk for severe COVID-19 and poor outcomes (ICU admittance, death) following CoV-2 infection [16,17,18]

Methods

Results

Conclusion