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

Year: 2026

Type: article

Abstract: Introduction: 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). Methods: -amplified SARS-CoV-2. Samples were collected between June 2020 and April 2022, with sample sizes based on primary sample availability and independent experiments. Results: 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. Discussion: 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.

Source: Frontiers in Cellular and Infection Microbiology

DOI: 10.3389/fcimb.2026.1976945