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  3. NETosis promotes chronic inflammation and fibrosis in systemic lupus erythematosus and COVID-19

NETosis promotes chronic inflammation and fibrosis in systemic lupus erythematosus and COVID-19

  • Clin Immunol. 2023 Jul 5;109687. doi: 10.1016/j.clim.2023.109687.
Huiqing Lin 1,  Jiejie Liu 2,  Ning Li 1,  Birong Zhang 3,  Van Dien Nguyen 3,  Peipei Yao 4,  Jiangpeng Feng 2,  Qianyun Liu 1,  Yu Chen 2,  Guang Li 5,  You Zhou 6,  Li Zhou 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology, Department of Thoracic Surgery, Renmin Hospital, Wuhan University, Wuhan 430060, China.
  • 2 State Key Laboratory of Virology, Modern Virology Research Center, RNA Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 3 Systems Immunity Research Institute, Cardiff University, Cardiff CF14 4XN, UK; Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
  • 4 State Key Laboratory of Virology, Modern Virology Research Center, RNA Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China; Institute for Vaccine Research, Animal Bio-Safety Level III Laboratory at Center for Animal Experiments, Wuhan University School of Medicine, Wuhan 430071, China.
  • 5 Department of Critical Care Medicine, Renmin Hospital, Wuhan University, Wuhan 430060, China. Electronic address: guangli@whu.edu.cn.
  • 6 Systems Immunity Research Institute, Cardiff University, Cardiff CF14 4XN, UK; Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK. Electronic address: zhouy58@cardiff.ac.uk.
  • 7 State Key Laboratory of Virology, Modern Virology Research Center, RNA Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China; Institute for Vaccine Research, Animal Bio-Safety Level III Laboratory at Center for Animal Experiments, Wuhan University School of Medicine, Wuhan 430071, China. Electronic address: zhouli_jerry@whu.edu.cn.
PMID: 37419296 DOI: 10.1016/j.clim.2023.109687
Abstract

Pulmonary fibrosis, a serious complication of systemic lupus erythematosus (SLE) and coronavirus disease 2019 (COVID-19), leads to irreversible lung damage. However, the underlying mechanism of this condition remains unclear. In this study, we revealed the landscape of transcriptional changes in lung biopsies from individuals with SLE, COVID-19-induced pulmonary fibrosis, and idiopathic pulmonary fibrosis (IPF) using histopathology and RNA Sequencing, respectively. Despite the diverse etiologies of these diseases, lung expression of matrix metalloproteinase genes in these diseases showed similar patterns. Particularly, the differentially expressed genes were significantly enriched in the pathway of neutrophil extracellular trap formation, showing similar enrichment signature between SLE and COVID-19. The abundance of Neutrophil extracellular traps (NETs) was much higher in the lungs of individuals with SLE and COVID-19 compared to those with IPF. In-depth transcriptome analyses revealed that NETs formation pathway promotes epithelial-mesenchymal transition (EMT). Furthermore, stimulation with NETs significantly up-regulated α-SMA, Twist, Snail protein expression, while decreasing the expression of E-cadherin protein in vitro. This indicates that NETosis promotes EMT in lung epithelial cells. Given drugs that are efficacious in degrading damaged NETs or inhibiting NETs production, we identified a few drug targets that were aberrantly expressed in both SLE and COVID-19. Among these targets, the JAK2 Inhibitor Tofacitinib could effectively disrupted the process of NETs and reversed NET-induced EMT in lung epithelial cells. These findings support that the NETs/EMT axis, activated by SLE and COVID-19, contributes to the progression of pulmonary fibrosis. Our study also highlights that JAK2 as a potential target for the treatment of fibrosis in these diseases.

Keywords

COVID-19; Epithelial to mesenchymal transition (EMT); Neutrophil extracellular traps (NETs); Pulmonary fibrosis; Systemic lupus erythematosus.

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