Abstract
Maternofetal pathogen transmission is partially controlled at the level of the maternal uterine mucosa at the fetal implantation site (the decidua basalis), where maternal and fetal cells are in close contact. Toll-like receptors (TLRs) may play an important role in initiating rapid immune responses against pathogens in the decidua basalis, however the tolerant microenvironment should be preserved in order to allow fetal development. Here we investigated the expression and functionality of TLRs expressed by decidual macrophages (dMs) and NK cells (dNKs), the major decidual immune cell populations. We report for the first time that both human dMs and dNK cells express mRNAs encoding TLRs 1-9, albeit with a higher expression level in dMs. TLR2, TLR3, and TLR4 protein expression checked by flow cytometry was positive for both dMs and dNK cells. In vitro treatment of primary dMs and dNK cells with specific TLR2, TLR3, TLR4, TLR7/8, and TLR9 agonists enhanced their secretion of pro- and anti-inflammatory cytokines, as well as cytokines and chemokines involved in immune cell crosstalk. Only dNK cells released IFN-γ, whereas only dMs released IL-1β, IL-10, and IL-12. TLR9 activation of dMs resulted in a distinct pattern of cytokine expression compared to the other TLRs. The cytokine profiles expressed by dMs and dNK cells upon TLR activation are compatible with maintenance of the fetotolerant immune environment during initiation of immune responses to pathogens at the maternofetal interface.
Highlights
The maternofetal interface is a unique anatomical site, in that it maintains a state of local immune tolerance to the semiallogenic fetus while simultaneously ensuring host defenses against microbial pathogens
In decidual macrophages (dMs), TLR4, TLR6, TLR8, and TLR9 mRNA expression was lower than TLR1, TLR2, TLR5, and TLR7 mRNA expression, and TLR3 mRNA was the most strongly expressed (Figure 1A)
TLR9 stimulation led to a statistically significant increase in IL-6 and IL-8 secretion in all the samples (Figure 2E and Table 3). These results show that TLR2, TLR3, TLR4, TLR7/8, and TLR9 are functional in dMs, as their activation with specific agonists induces statistically significant increases in the secretion of at least one pro-inflammatory cytokine (IL-1β, TNF-α, IL-6, and/or IL-8)
Summary
The maternofetal interface is a unique anatomical site, in that it maintains a state of local immune tolerance to the semiallogenic fetus while simultaneously ensuring host defenses against microbial pathogens. Viruses are present at the maternofetal interface (Chouquet et al, 1997; Fidler et al, 2004; Picone et al, 2013). In utero transmission of these viruses is relatively rare and seems to be controlled (Chouquet et al, 1997; Fidler et al, 2004; Picone et al, 2013). To ensure host defenses against invading pathogens, the maternofetal interface must efficiently recognize a broad range of pathogen-associated molecular patterns (PAMPs) in order to provide an immediate immune response
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