Characterising the Expression and Transcriptional Regulation of Peroxidasin and Peroxidasin-like in the Lung During a Cytokine Storm

Abstract

Peroxidasin (PXDN) and Peroxidasin-like (PXDNL) proteins have recently been shown to have emerging roles in vascular disease. PXDN is secreted into the extracellular matrix (ECM) where it catalyses collagen IV crosslinking and PXDNL is thought to antagonise the function of PXDN. PXDN is predominantly expressed in the cardiovascular system, lung and smooth muscle, while PXDNL expression is found in heart muscle. As these expression patterns correlate with human tissues most affected during SARS-CoV-2 infection, this study aimed to investigate gene expression changes of PXDN and PXDNL under conditions that mimic inflammatory responses. Immunofluorescences microscopy and western botting showed that PXDN and PXDNL expression patterns are altered in response to cytokines (TNF-α, IL-1β, IFN-γ and IL-6) by treating A549 cells with 25 ng/ml of each cytokine for 24 hours, with notable increases in expression in response to IFN-γ and IL-6. Further analysis by chromatin immunoprecipitation (ChIP)-PCR indicated that transcriptional regulation of PXDN in the presence of IL-6 and IFN-γ is controlled, at least in part, by STAT3 and by NF-κB in presence of IFN-γ. PXDNL is regulated by STAT3 in response to IL-6. These findings indicate that PXDN and PXDNL may be involved in inflammation, and we identified a novel pathway of their transcriptional regulation.