Sex steroids differentially modulate SARS-CoV-2-induced inflammatory responses in endothelial and immune cells

Sex-related differences in coronavirus disease 2019 (COVID-19) severity suggest an important role for sex steroids in regulating immune and endothelial responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Receptor expression, inflammatory signaling, and monocyte transendothelial migration were assessed by RT-PCR, immunoblotting, and Boyden chamber assay, respectively. HULEC-5a and primary human immune cells were exposed to in vitro-amplified SARS-CoV-2. Samples were collected between June 2020 and April 2022, with sample sizes based on primary sample availability and independent experiments.

SARS-CoV-2 differentially regulates estrogen receptor gene expression, decreasing it in endothelial cells (p<0.05) while increasing it in immune cells (p<0.01). SARS-CoV-2 generally activated inflammatory signaling pathways, including NFκB, STAT3, and p38 MAPK, in THP-1 monocytic cells (up to 1.9-fold). The NFκB response was augmented by the androgen receptor agonist dihydrotestosterone (DHT, 44.6%) and attenuated by the androgen receptor antagonist flutamide (44.1%). In endothelial cells, DHT twice reduced SARS-CoV-2 activation of the p38 MAPK signaling pathway. β-estradiol inhibited (2.2-fold), whereas DHT stimulated (4.9-fold) NFκB signaling pathway in neutrophils isolated from patients with COVID-19. SARS-CoV-2 activation of inflammatory signaling pathways deteriorates over time in monocytes from patients with COVID-19 (p<0.05). Furthermore, DHT significantly increased trans-endothelial migration of monocytes (p<0.001) and detachment of SARS-CoV-2 exposed endothelial cells (p<0.01), suggesting a potential role for androgen-responsive pathways in endothelial dysfunction and immune cell trafficking.

These findings elucidate the molecular mechanisms driving male-biased COVID-19 severity and underscore the potential of targeting androgen-responsive pathways as a therapeutic strategy to mitigate severe viral inflammation and endothelial dysfunction.