Inhibition of Androgen Receptor Signaling Reduces Inflammation in the Lung with SARS-CoV-2 Infection Through Dampening IL6 Signaling

Dissecting the mechanism of the inflammatory response to SARS-CoV-2 infection is critical for establishing therapeutic options. Increased mortality associated with COVID-19 in male patients could be orchestrated through the androgen receptor (AR) signaling and activation of the immune response. We report a direct link between AR signaling and interleukin 6 (IL6) expression through AR antagonist, enzalutamide, and RNA interference studies. Our analysis revealed AR signaling in bronchoalveolar and non-small cell lung carcinoma cells are sensitive to the androgen ligand, R1881. Disruption of liganded-AR interactions with enzalutamide resulted in a significant decrease in IL6 expression and increased c-MAF expression. By reanalyzing public datasets, we discovered SARS-CoV-2 infection of lung cells is associated with increased IL6 expression and decreased c-MAF expression. Modeling of the regulatory transcriptional network from SARSCoV-2 infected lung cells implicates IL6 to be the most connected hub gene, controlled through transcription factor c-MAF, with concomitant cytokine and viral-mediated complement activated pathways. Taken together, our results suggest enzalutamide may be useful in reducing inflammatory genes by disrupting AR signaling cascade in the lungs of COVID-19 patients.Funding Information: This study was funded in part by Astellas- Pfizer and from the University of Wisconsin School of Medicine and Public Health and the University of Wisconsin Carbone Cancer Center Support Grant P30 CA014520..Declaration of Interests: The authors declare no potential conflicts of interest.Ethics Approval Statement: The study did not involve human subjects. All experiments were approved and are compliant by the Office of the Vice Chancellor for Research and Graduate Education Biosafety institutional committee at the University of Wisconsin- Madison Biosafety.