title: Human gestation-associated tissues express functional cytosolic nucleic acid sensing pattern recognition receptors.
abstract: 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.
authors.affiliation: Institute of Life Science, Swansea University Medical School.
authors.forename: A H
authors.identifier: 0000-0002-4650-4672
authors.initials: AH
authors.lastname: Bryant
authors.affiliation: Institute of Life Science, Swansea University Medical School.
authors.forename: G E
authors.initials: GE
authors.lastname: Menzies
authors.affiliation: Institute of Life Science, Swansea University Medical School.
authors.forename: L M
authors.initials: LM
authors.lastname: Scott
authors.affiliation: Department of Histopathology, Abertawe Bro Morgannwg University Health Board, Swansea, Wales, UK.
authors.forename: S
authors.initials: S
authors.lastname: Spencer-Harty
authors.affiliation: Institute of Life Science, Swansea University Medical School.
authors.forename: L B
authors.initials: LB
authors.lastname: Davies
authors.affiliation: Institute of Life Science, Swansea University Medical School.
authors.forename: R A
authors.initials: RA
authors.lastname: Smith
authors.affiliation: Institute of Life Science, Swansea University Medical School.
authors.forename: R H
authors.initials: RH
authors.lastname: Jones
authors.affiliation: Institute of Life Science, Swansea University Medical School.
authors.forename: C A
authors.initials: CA
authors.lastname: Thornton
mesh_terms: D000071457:DEAD Box Protein 58 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D000072640:Interferon-Induced Helicase, IFIH1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D009696:Nucleic Acids / Q000276:immunology; D010920:Placenta / Q000276:immunology*; D011070:Poly I-C / Q000276:immunology; D011247:Pregnancy; D020365:RNA Helicases / Q000378:metabolism*; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition / Q000276:immunology*; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*
chemical_list: C508606:CXCL8 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D009696:Nucleic Acids; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition; D051193:Toll-Like Receptors; C520569:DHX58 protein, human; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D000072640:Interferon-Induced Helicase, IFIH1; D020365:RNA Helicases; D011070:Poly I-C
keywords: hierarchical clustering; inflammation; pattern recognition receptors; reproductive immunology; viral