Therapeutic application of estrogen for COVID-19: Attenuation of IL-6 and SARS-CoV-2 spike protein stimulated NOX2 activation and ROS production in endothelial cells

Youn, Ji Youn; Zhang, Yixuan; Wu, Yusi; Cannesson, Maxime; Cai, Hua

The outbreak of COVID-19 has remained uncontained with urgent need for robust therapeutics. Males are more susceptible than females, and more often to develop into severe cases with higher mortality. This predisposition is potentially linked to higher prevalence of cigarette smoking. Nonetheless, we found for the first time that cigarette smoking extract (CSE) had no effect on angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) expression in endothelial cells. The otherwise observed worse outcomes in smokers is likely linked to baseline respiratory diseases associated with chronic smoking. Instead, we hypothesized that estrogen mediated protection might underlie less severe disease in females. Of note, endothelial inflammation and barrier dysfunction are major mediators of disease progression, and development of acute respiratory distress syndrome (ARDS) and multi-organ failure in patients with COVID-19. Therefore, we investigated the protective effects of estrogen on endothelial cells against oxidative stress induced by interleukin-6 (IL-6) and SARS-CoV-2 spike protein (S protein). Indeed, 17β-estradiol completely reversed IL-6 and S protein-induced selective activation of NADPH oxidase isoform 2 (NOX2), reactive oxygen species (ROS) production, ACE2 upregulation and induction of pro-inflammatory gene monocyte chemoattractant protein-1 (MCP-1) in endothelial cells to effectively attenuate endothelial cell dysfunction. Of note, co-treatment with CSE had no additional effects on S protein stimulated endothelial oxidative stress, again indicating that current smoking status is likely unrelated to more severe disease in chronic smokers. These data indicate that estrogen may serve as a novel therapy for patients with COVID-19 via inhibition of initial viral responses and attenuation of cytokine storm induced endothelial dysfunction, to substantially alleviate severity of the disease and mortality, especially in men. Short-term application of estrogen may therefore be readily used in the clinical management of COVID-19 as a robust therapeutic option.