Crosstalk between estrogen, dendritic cells, and SARS-CoV-2 infection

Abstract

The novel coronavirus disease 2019 (Covid-19) first appeared in Wuhan and has so far killed more than four million people worldwide. Men are more affected than women by Covid-19, but the cellular and molecular mechanisms behind these differences are largely unknown. One plausible explanation is that differences in sex hormones could partially account for this distinct prevalence in both sexes. Accordingly, several papers have reported a protective role of 17β-estradiol during Covid-19, which might help explain why women appear less likely to die from Covid-19 than men. 17β-estradiol is the predominant and most biologically active endogenous estrogen, which signals through estrogen receptor α, estrogen receptor β, and G protein-coupled estrogen receptor 1. These receptors are expressed in mature cells from the innate and the adaptive immune system, particularly on dendritic cells (DCs), suggesting that estrogens could modulate their effector functions. DCs are the most specialized and proficient antigen-presenting cells, acting at the interface of innate and adaptive immunity with a powerful capacity to prime antigen-specific naive CD8+ T cells. DCs are richly abundant in the lung where they respond to viral infection. A relative increase of mature DCs in broncho-alveolar lavage fluids from Covid-19 patients has already been reported. Here we will describe how SARS-CoV-2 acts on DCs, the role of estrogen on DC immunobiology, summarise the impact of sex hormones on the immune response against Covid-19, and explore clinical trials regarding Covid-19.

Keywords: SARS-CoV-2; dendritic cells; estrogen.

FIGURE 1

(a) Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) structure. SARS‐CoV‐2 is a virus enveloped with a nonsegmented positive‐sense single‐stranded ribonucleic acid ((+)ss‐RNA) genome. Their genome codes for four major proteins: spike protein, envelope protein, membrane protein, nucleocapsid, and accessory proteins. (b). How SARS‐CoV‐2 acts on dendritic cells. When SARS‐CoV‐2 infects the respiratory tract, the host innate immune system detects viral infection by using pattern recognition receptors, including toll‐like receptor (TLR), to recognize damage‐associated molecular patterns and pathogen‐associated molecular patterns, like‐proteins, lipoproteins, and nucleic acids of viral origin. The plasmacytoid dendritic cells (pDCs) could recognize ss‐RNA viruses via TLR7. Subsequently the interferon regulatory factor (IRF)‐7 is activated to induce the production of pro‐inflammatory cytokines, such as interferon (INF)‐α. (c). Estrogen receptors (ERs). Following interaction with its ligand (E), the ER can modulate cellular function through nuclear genomic (1,2,3) or non‐genomic (4) mechanisms. (1) Nuclear E‐ER binds directly to estrogen receptor element in target gene promoters. (2) Nuclear E‐ER is tethered through protein‐protein interactions to a transcription factor complex (TF) that contacts the target gene promoter. (3) Growth factors activate protein‐kinase cascades, leading to phosphorylation (P) and activation of nuclear ER at the target gene. (4) Membrane E‐ER complexes activate protein‐kinase cascades, leading to altered functions of proteins in the cytoplasm (e.g., activation of eNOS) or the regulation of gene expression through phosphorylation (P) and activation of a TF. (d). How estrogen acts on dendritic cells. The culture of bone marrow cells in the presence of granulocyte‐macrophage colony‐stimulating factor, has shown the crucial role of estrogen (E) in the culture medium in promoting the development of CD103⁺ cDCs and CD11b⁺ cDCs. The CD11b⁺ cDC subset displayed higher levels of cell surface CD86, exhibiting superior ability to induce the proliferation of naive CD4⁺ T cells. However, estrogen decreases the absolute number of pDCs, led to a more mature phenotype development and an enhanced capacity to produce interleukin (IL)‐12 in response to TLR9 stimulation. Subsequently, the high levels of IL‐12 induce the differentiation of Th1 cells. The higher levels of estrogen also enhance the TLR7‐dependent production of IFN‐α by pDCs, increasing the immune response against the virus., (e). The effect of 17β‐estradiol levels on angiotensin‐converting enzyme (ACE)2 and transmembrane serine protease (TMPRSS)2 expression. Pre‐treatment of the VERO E6 cell line with 17β‐estradiol showed that estrogen significantly downregulated TMPRSS2 messenger RNA (mRNA) expression. Similarly, normal human bronchial epithelial cells pre‐treated with 17β‐estradiol expressed lower levels of ACE2 mRNA. In spite of the downregulation of TMPRSS2 mRNA and ACE2 mRNA, it might not translate into a reduction of protein expression at the cell surface (red arrow). Created with BioRender.com

FIGURE 2

Sex differences during novel coronavirus disease 2019 (Covid‐19). Sex differences from confirmed cases, intensive care unit admissions, and deaths during Covid‐19. There are differences between sexes with male patients showing higher morbidity and mortality than female patients. The data was obtained from Global Health 5050 on 17^th August 2021

FIGURE 3

Active studies of drugs that interfere with cell signaling triggered by sex hormones., , , , , , , , , , , , , , , , , Adapted from