Sex steroids differentially modulate SARS-CoV-2-induced inflammatory responses in endothelial and immune cells.
4 affiliations
- 1Department of Molecular Oncology, Clinic of Hematology, University Clinical Center of Serbia, Belgrade, Serbia.
- 2Department of Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia.
- 3Department of Molecular Oncology, Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia.
- 4Department of Microbiology, University Clinical Centre of Serbia, Belgrade, Serbia.
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
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.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.
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BibTeX
@article{bizicradulovic2026steroids,
title = {{Sex steroids differentially modulate SARS-CoV-2-induced inflammatory responses in endothelial and immune cells.}},
author = {Sandra Bižić-Radulović and Tijana Subotički and Ana Kovačević and Emilija Živković and Olga Popović and Olivera Mitrović-Ajtić and Miloš Diklić and Snežana Jovanović and Vladan P Čokić and Bojana Beleslin-Čokić},
journal = {Frontiers in cellular and infection microbiology},
year = {2026},
month = oct,
doi = {10.3389/fcimb.2026.1976945},
url = {https://europepmc.org/article/MED/42952489},
note = {CC BY},
}
RIS
TY - JOUR
TI - Sex steroids differentially modulate SARS-CoV-2-induced inflammatory responses in endothelial and immune cells.
AU - Sandra Bižić-Radulović
AU - Tijana Subotički
AU - Ana Kovačević
AU - Emilija Živković
AU - Olga Popović
AU - Olivera Mitrović-Ajtić
AU - Miloš Diklić
AU - Snežana Jovanović
AU - Vladan P Čokić
AU - Bojana Beleslin-Čokić
PY - 2026
DA - 2026/10/14
JO - Frontiers in cellular and infection microbiology
DO - 10.3389/fcimb.2026.1976945
UR - https://europepmc.org/article/MED/42952489
AB - 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 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.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.
SN - 2235-2988
ER -