Human gestation-associated tissues express functional cytosolic nucleic acid sensing pattern recognition receptors

Abstract

Summary The role of viral infections in adverse pregnancy outcomes has gained interest in recent years. Innate immune pattern recognition receptors (PRRs) and their signalling pathways, that yield a cytokine output in response to pathogenic stimuli, have been postulated to link infection at the maternal–fetal interface and adverse pregnancy outcomes. The objective of this study was to investigate the expression and functional response of nucleic acid ligand responsive Toll‐like receptors (TLR‐3, −7, −8 and −9), and retinoic acid‐inducible gene 1 (RIG‐I)‐like receptors [RIG‐I, melanoma differentiation‐associated protein 5 (MDA5) and Laboratory of Genetics and Physiology 2(LGP2)] in human term gestation‐associated tissues (placenta, choriodecidua and amnion) using an explant model. Immunohistochemistry revealed that these PRRs were expressed by the term placenta, choriodecidua and amnion. A statistically significant increase in interleukin (IL)‐6 and/or IL‐8 production in response to specific agonists for TLR‐3 (Poly(I:C); low and high molecular weight), TLR‐7 (imiquimod), TLR‐8 (ssRNA40) and RIG‐I/MDA5 (Poly(I:C)LyoVec) was observed; there was no response to a TLR‐9 (ODN21798) agonist. A hierarchical clustering approach was used to compare the response of each tissue type to the ligands studied and revealed that the placenta and choriodecidua generate a more similar IL‐8 response, while the choriodecidua and amnion generate a more similar IL‐6 response to nucleic acid ligands. These findings demonstrate that responsiveness via TLR‐3, TLR‐7, TLR‐8 and RIG‐1/MDA5 is a broad feature of human term gestation‐associated tissues with differential responses by tissue that might underpin adverse obstetric outcomes.

Enhanced expression of IFI16 and RIG-I in human third-trimester placentas following HSV-1 infection

“…These results showed that BVDV has the ability to cross the placenta and infect the fetus due to insufficient development of the fetal immune system and that RNA helicases RIG-I and MDA5 can be induced in infected fetuses. RIG-I, as well as MDA5, TLR-3, TLR-7 and TLR-8, were also found to be expressed by the term placenta, choriodecidua and amnion in a second study [31]. Our results may indicate that RIG-I activate in chorionic villi and decidua the same intracellular signalling pathway as IFI16.…”

“…It was described previously that RIG-I acts in parallel with DAI in an RNA polymerase IIIdependent manner to initiate inflammatory and antiviral glial responses to HSV-1 infection [47]. RIG-I, as well as MDA5, TLR-3, TLR-7 and TLR-8, were also found to be expressed by the term placenta, choriodecidua and amnion in a second study [31]. These results showed that BVDV has the ability to cross the placenta and infect the fetus due to insufficient development of the fetal immune system and that RNA helicases RIG-I and MDA5 can be induced in infected fetuses.…”

“…PRRs are key components of the innate and adaptive immune responses and play a key role in the maternal-fetal interface [31][32][33][34]. We have shown that the IFI16 expression at both mRNA and protein levels was elevated significantly in third-trimester human placentas infected with HSV-1 ex vivo compared to mock-infected explants.…”

The immunology of the fetal–placental unit comes of age

“…A still-controversial uterine microbiota could help to model the interaction between the feto-placental unit and the maternal immune system [1,12]. [13,14]), competent to recognize microbial constituents translocated within the blood and more in general to integrate sterile and microbial stimuli. It might be relevant that decidual cells express innate pattern recognition receptors (e.g.…”

“…It might be relevant that decidual cells express innate pattern recognition receptors (e.g. [13,14]), competent to recognize microbial constituents translocated within the blood and more in general to integrate sterile and microbial stimuli. Because of the signals generated by the feto-placental unit and by the decidua (bioactive microvesicles, hormones, cytokines, etc.…”