Cytokines as drivers: Unraveling the mechanisms of epithelial-mesenchymal transition in COVID-19 lung fibrosis

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), like other viruses, can induce proliferation of myofibroblasts and even lead to fibrosis in the lung. Epithelial-mesenchymal transition (EMT) is thought to play an essential role in the pathogenesis of Coronavirus disease 19 (COVID-19). EMT is originally a critical process that regulates the development of different tissues in the embryo, but in inflammatory situations, EMT tries to be activated again to control inflammation or even heal inflammatory damage. However, in pathological situations, such as chronic viral infections (e.g., COVID-19) or pulmonary fibrosis initiation, this benign healing transforms into sinister nature, pushing the lung into the fibrotic process. Notably, the cytokines released by inflammatory cells and the chronic inflammatory microenvironment shared by fibrotic cells promote each other as critical factors in the induction of pathological EMT. In the induction of SARS-CoV-2 virus, cytokines are an essential mediator of EMT transformation, and a summary of whether COVID-19 patients, during the infection phase, have many persistent inflammatory mediators (cytokines) that are a causative factor of EMT has not yet appeared. The following common signaling drivers, including Transforming growth factor beta (TGF-β), cytokines, Notch signaling pathway, Wnt and hypoxia signaling pathways, drive the regulation of EMT. In this review, we will focus on 3 key EMT signaling pathways: TGF-β, Leucine zipper transcription factor like 1 (LZTFL1) and the common interleukin family expressed in the lung. TGF-β-induced SNAIL and LZTFL1 were identified as regulatory EMT in COVID-19. For cytokines, the interleukin family is a common inducer of EMT and plays an essential role in the formation of the microenvironment of fibrosis. We sought to demonstrate that cytokines act as "communicators" and build the "microenvironment" of fibrosis together with EMT as a "bridge" to induce EMT in fibrosis. The mechanisms utilized by these two pathways could serve as templates for other mesenchymal transformations and provide new potential therapeutic targets.

Keywords: COVID-19; Epithelial-mesenchymal transition (EMT); Leucine zipper transcription factor like 1 (LZTFL1); Transforming growth factor beta 1 (TGF-β1).