Desterke Christophe, Turhan Ali G, Bennaceur-Griscelli Annelise, Griscelli Frank
INSERM UA9- University Paris-Saclay, Institut André Lwoff, Bâtiment A CNRS, 7 rue Guy Moquet, 94800 Villejuif, France.
ESTeam Paris Sud, INGESTEM National IPSC Infrastructure, University Paris-Saclay, 94800 Villejuif, France.
iScience. 2020 Oct 23;23(10):101611. doi: 10.1016/j.isci.2020.101611. Epub 2020 Sep 25.
The molecular mechanisms of cytokine storm in patients with severe COVID-19 infections are poorly understood. To uncover these events, we performed transcriptome analyses of lung biopsies from patients with COVID-19, revealing a gene enrichment pattern similar to that of PPARγ-knockout macrophages. Single-cell gene expression analysis of bronchoalveolar lavage fluids revealed a characteristic trajectory of PPARγ-related disturbance in the CD14+/CD16+ cells. We identified a correlation with the disease severity and the reduced expression of several members of the PPARγ complex such as EP300, RXRA, RARA, SUMO1, NR3C1, and CCDC88A. ChIP-seq analyses confirmed repression of the PPARγ-RXRA-NR3C1 cistrome in COVID-19 lung samples. Further analysis of protein-protein networks highlighted an interaction between the PPARγ-associated protein SUMO1 and a nucleoprotein of the SARS virus. Overall, these results demonstrate for the first time the involvement of the PPARγ complex in severe COVID-19 lung disease and suggest strongly its role in the major monocyte/macrophage-mediated inflammatory storm.
严重新型冠状病毒肺炎（COVID-19）感染患者细胞因子风暴的分子机制目前尚不清楚。为了揭示这些情况，我们对COVID-19患者的肺活检组织进行了转录组分析，发现了一种与PPARγ基因敲除巨噬细胞相似的基因富集模式。对支气管肺泡灌洗液的单细胞基因表达分析揭示了CD14+/CD16+细胞中PPARγ相关紊乱的特征轨迹。我们发现疾病严重程度与PPARγ复合物的几个成员（如EP300、RXRA、RARA、SUMO1、NR3C1和CCDC88A）表达降低之间存在相关性。染色质免疫沉淀测序（ChIP-seq）分析证实了COVID-19肺样本中PPARγ-RXRA-NR3C1顺反子组被抑制。对蛋白质-蛋白质网络的进一步分析突出了PPARγ相关蛋白SUMO1与严重急性呼吸综合征（SARS）病毒核蛋白之间的相互作用。总体而言，这些结果首次证明了PPARγ复合物参与了严重的COVID-19肺部疾病，并有力地表明了其在主要单核细胞/巨噬细胞介导的炎症风暴中的作用。
