[저자] 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
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.
All Keywords
【저자키워드】 COVID-19, ARDS, Cytokine storm, pulmonary fibrosis, vascular dysfunction, autotaxin (ATX; ENPP2), lysophosphatidic acid (LPA), dendritic cells (DCs), 【초록키워드】 Dexamethasone, Treatment, Inflammation, Biomarkers, Hospitalization, IL-6, fibrosis, endothelial damage, mechanically ventilated patients, dendritic cells, Nasopharyngeal swab, COVID-19 pathogenesis, hyperinflammation, RNA sequencing, immune cells, Single Cell, dataset, pulmonary injury, vascular dysfunction, expression, homeostasis, COVID-19 patients, Nasopharyngeal swab samples, Signaling, Immune cell, Autotaxin, therapeutic option, Therapeutic benefit, Serum level, suppression, severe COVID-19 patients, cohorts, mechanically ventilated, therapeutic benefits, nasopharyngeal swab sample, mRNA level, pharmacological, ENPP2, independent, Extracellular, shown, include, pathologic, reduced, functional, suggested, correlated, multifunctional, LPA, pleiotropic, mechanically ventilated patient, scale analysis, secreted, 【제목키워드】 function, Level, Increased, Impaired,
Autotaxin(ATX; ENPP2)은 분비된 리소포스포리파제 D로, 다발성 신호전달 인지질인 리소포스파티딘산(LPA)의 세포외 생산을 촉매합니다. 유전 및 약리학 연구는 이전에 폐 손상, 염증 및 섬유증에서 ATX 및 LPA 신호 전달에 대한 병리학적 역할을 확립했습니다. 여기에서 COVID-19 환자의 비인두 면봉 샘플에서 면역 세포에서 증가된 ENPP2 mRNA 수준이 검출되었고, 중증 COVID-19 환자에서 증가된 ATX 혈청 수준이 발견되었습니다. ATX 혈청 수준은 IL-6 및 내피 손상 바이오마커의 증가된 혈청 수준과 상관관계가 있었으며, 이는 ATX/LPA 축과 코로나19의 과염증 및 관련 혈관 기능 장애의 상호 작용을 시사합니다. 따라서 기계적으로 환기되는 환자의 덱사메타손(Dex) 치료는 두 개의 독립적인 코호트에서 볼 수 있듯이 ATX 수준을 감소시켰으며, 이는 Dex의 치료적 이점이 ATX 억제를 포함함을 나타냅니다. 또한, 여러 단일 세포 RNA 시퀀싱 데이터 세트에 대한 대규모 분석은 COVID-19에서 ENPP2의 발현 환경을 보여주었고 COVID-19에서 수치적 및 기능적 결함을 모두 나타내는 수지상 세포의 항상성에서 ATX의 역할을 추가로 제안했습니다. 따라서 ATX는 COVID-19 발병 기전에서 다기능 역할을 할 가능성이 있으며, 이는 약리학적 표적이 입원 중 및 입원 후에 추가 치료 옵션을 나타낼 수 있음을 시사합니다.