Estradiol‐regulated innate antiviral responses of human endometrial stromal fibroblasts

Abstract

Problem: The contribution of fibroblasts to innate immune protection of the human female reproductive tract (FRT) against viral pathogens is relatively unknown. Method of Study: Endometrial (EM), endocervical (Cx), and ectocervical (ECx) fibroblasts were isolated from hysterectomy patients and grown in vitro. Fibroblasts were treated with the viral mimic poly (I:C) in the presence or absence of the sex hormone estradiol (E2), with gene expression measured by real-time RT-PCR and protein secretion by ELISA. Results: Poly (I:C) induced the expression of the interferon-stimulated genes (ISG) MxA, OAS2 and APOBEC3G, and the cytokines MCP-1, IL-8, IL-6, CCL20, IFNβ and RANTES by fibroblasts from all three sites. ISG upregulation was dependent upon Type I IFN signaling. E2 inhibited the poly (I:C)-induced upregulation of MxA and OAS2 in EM fibroblasts, but not Cx or ECx fibroblasts. E2 upregulated SDF-1α by EM fibroblasts but had no effect on secretion of other cytokines either alone or in the presence of poly (I:C). Conditioned media (CM) from poly (I:C)-treated or E2-treated fibroblasts significantly reduced HIV infection of CD4+ T cells. Conclusions: Stromal fibroblasts represent a level of innate immune protection against viral pathogens in the FRT beyond that seen with epithelial cells and immune cells. Our findings indicate that fibroblasts FRT are selectively responsive to E2, capable of initiating an antiviral response against viral pathogens, and may play a role in preventing HIV infection of CD4+ T cells.

The impact of aging on innate and adaptive immunity in the human female genital tract

“…While primarily considered structural cells, they are key players in the innate immune response within the FRT (Wira et al, 2015). Fibroblasts express multiple PRRs, including TLR2, TLR3, TLR4, TLR5, TLR6, TLR9, RIG‐I, and MDA5, with endometrium fibroblasts generally expressing higher PRR levels than other sites in the FRT (Patel et al, 2018b; Patel Shen, & Wira, 2018). They mount innate immune responses against a broad range of incoming pathogens characterized by increased secretion of inflammatory cytokines and chemokines, leading to increased chemotaxis of immune cells (Patel et al, 2018b; Patel Shen, & Wira, 2018).…”

“…Fibroblasts express multiple PRRs, including TLR2, TLR3, TLR4, TLR5, TLR6, TLR9, RIG‐I, and MDA5, with endometrium fibroblasts generally expressing higher PRR levels than other sites in the FRT (Patel et al, 2018b; Patel Shen, & Wira, 2018). They mount innate immune responses against a broad range of incoming pathogens characterized by increased secretion of inflammatory cytokines and chemokines, leading to increased chemotaxis of immune cells (Patel et al, 2018b; Patel Shen, & Wira, 2018). FRT fibroblasts secrete Type I and Type III interferons (IFNs) and thus induce an antiviral state in adjacent cells (Patel et al, 2018b; Patel Shen, & Wira, 2018).…”

Stromal Heterogeneity in the Human Proliferative Endometrium—A Single-Cell RNA Sequencing Study

“…Other genes in this population have also been associated with epithelial–stromal interactions, as well as innate immune responses, specifically M2 anti-inflammatory macrophage polarization ( PTPRS , PAQRF , PRDM1 , AXL and FOLR2 ) [ 32 , 33 , 34 , 35 ]. Similarly, in the ISG15+ population, most genes are involved in interferon signaling and innate immunity functions ( ISG15 , IF16 , MX1 , OAS1 , IF144L , OAS3 , OAS2, MX2, IFIT3 ) [ 36 , 37 ], suggestive of an activated stromal cell state/a subtype active in immunomodulation.…”

The Dual Role of the Immune Response in Reproductive Organs During Zika Virus Infection

“…In addition, relevant future studies are needed to understand the role of hormones that regulated the menstrual cycle and the effect on sexual transmission of ZIKV in the FRT. Recently, it has been suggested that estradiol is associated with activation of the innate immune mechanism and initiation of the antiviral responses, and that the modulation by sexual hormones results in alteration of a woman's susceptibility to HIV-1 and other infections (61, 63). The understanding about the role of hormones in different stages of menstrual cycle or pregnancy may help to resolve question on the mechanism of ZIKV to persist in the FRT (Figure 2).…”