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

Lin, Huiqing, Liu, Jiejie, Li, Ning, Zhang, Birong, Nguyen, Van Dien, Yao, Peipei, Feng, Jiangpeng, Liu, Qianyun, Chen, Yu, Li, Guang, Zhou, You ORCID: https://orcid.org/0000-0002-1743-1291 and Zhou, Li 2023. NETosis promotes chronic inflammation and fibrosis in systemic lupus erythematosus and COVID-19. Clinical Immunology 254 , 109687. 10.1016/j.clim.2023.109687

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Publisher:	Elsevier
ISSN:	1521-6616
Date of First Compliant Deposit:	23 July 2023
Date of Acceptance:	17 June 2023
Last Modified:	07 Nov 2024 05:00
URI:	https://orca.cardiff.ac.uk/id/eprint/161205

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