The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide administration. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.

C1q/TNF-Related Protein-3 (CTRP3) and CTRP13 are two newly discovered adipokines regulating glucose and lipid metabolism. But their role in type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) is still in infancy. The aim of this study was to investigate the associations of gene expression and serum levels of CTRP3 and CTRP13 with CAD, metabolic and inflammatory markers in patients with and without T2DM. Serum levels of CTRP3, CTRP13, adiponectin and inflammatory cytokines and their gene expression in peripheral blood mononuclear cells (PBMCs) were determined in 172 subjects categorized as group I (without T2DM and CAD), group II (with CAD but no T2DM), group III (with T2DM but no CAD) and group IV (with T2DM and CAD). Serum levels and gene expression of CTRP3, CTRP13 and adiponectin in the group I were higher compared to other groups. Inflammatory cytokines in the control group were lower than other groups too. CTRP3 serum levels have an independent association with BMI, smoking and CTRP3 gene expression; also CTRP13 serum levels has an independent association with BMI, HDL-C, insulin, HOMA-IR, HbA1c and TNF-α. Decreased serum levels of CTRP3 and CTRP13 were also associated with CAD. It appears that the decreased levels of CTRP3 and especially CTRP13 were associated with increased risk of T2DM and CAD. These findings suggest an emerging role of these adipokines in the pathogenesis of CAD, but further studies are necessary to establish this concept.

The recent emergence of SARS-CoV-2 and the subsequent COVID-19 pandemic have posed a public health crisis. Higher morbidity and mortality of men with COVID-19 may be explained by androgen-driven mechanisms. One such proposed mechanism is androgen regulation of pulmonary TMPRSS2, the host co-receptor for SARS-CoV-2. We find no evidence for increased TMPRSS2 mRNA expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide does not decrease pulmonary TMPRSS2 expression. Nevertheless, regardless of sex, smoking significantly increases the expression of TMPRSS2, which reverts back to never-smoker levels in former smokers. Finally, we show that in mouse models, despite equivalent AR transcript levels, males express markedly higher amounts of AR protein. If a similar sex-specific regulation of AR protein occurs in human lung, androgens could play important roles in clinical outcome of COVID-19 through mechanisms other than TMPRSS2 regulation.

The viral FLICE-like inhibitory protein (FLIP) protein from Kaposi sarcoma-associated herpesvirus activates the NF-κB pathway by forming a stable complex with a central region (amino acids 150–272) of the inhibitor of NF-κB kinase (IKK) γ subunits, thereby activating IKK. Cellular FLIP (cFLIP) forms are also known to activate the NF-κB pathway via IKK activation. Here we demonstrate that cFLIPL, cFLIPS, and their proteolytic product p22-FLIP all require the C-terminal region of NEMO/IKKγ (amino acids 272–419) and its ubiquitin binding function for activation of the IKK kinase (or kinase complex), but none form a stable complex with IKKγ. Our results further reveal that cFLIPL requires the linear ubiquitin chain assembly complex and the kinase TAK1 for activation of the IKK kinase. Similarly, cFLIPS and p22-FLIP also require TAK1 but do not require LUBAC. In contrast, these isoforms are both components of complexes that incorporate Fas-associated death domain and RIP1, which appear essential for kinase activation. This conservation of IKK activation among the cFLIP family using different mechanisms suggests that the mechanism plays a critical role in their function.