title: Local activation of uterine Toll-like receptor 2 and 2/6 decreases embryo implantation and affects uterine receptivity in mice.
abstract: Embryo implantation is a complex interaction between maternal endometrium and embryonic structures. Failure to implant is highly recurrent and impossible to diagnose. Inflammation and infections in the female reproductive tract are common causes of infertility, embryo loss, and preterm labor. The current work describes how the activation of endometrial Toll-like receptor (TLR) 2 and 2/6 reduces embryo implantation chances. We developed a morphometric index to evaluate the effects of the TLR 2/6 activation along the uterine horn (UH). TLR 2/6 ligation reduced the endometrial myometrial and glandular indexes and increased the luminal index. Furthermore, TLR 2/6 activation increased the proinflammatory cytokines such as interleukin (IL)-1beta and monocyte chemotactic protein (MCP)-1 in UH lavages in the preimplantation day and IL-1 receptor antagonist in the implantation day. The engagement of TLR 2/6 with its ligand in the UH during embryo transfer severely affected the rate of embryonic implantation (45.00% ± 6.49% vs. 16.69% ± 5.01%, P < 0.05, control vs. test, respectively). Furthermore, this interference with the embryo implantation process was verified using an in vitro model of human embryo implantation where trophoblast spheroids failed to adhere to a monolayer of TLR 2- and TLR 2/6-activated endometrial cells. The inhibition of TLR receptors 2 and 6 in the presence of their specific ligands restored the ability of the spheroids to bind to the endometrial cells. In conclusion, the activation of the innate immune system in the uterus at the time of implantation interfered with the endometrial receptivity and reduced the chances of implantation success.
authors.affiliation: Academic Unit of Reproductive and Developmental Medicine, The University of Sheffield, Sheffield, United Kingdom.
authors.forename: Javier Arturo
authors.initials: JA
authors.lastname: Sanchez-Lopez
authors.forename: Ignacio
authors.initials: I
authors.lastname: Caballero
authors.forename: Mehrnaz
authors.initials: M
authors.lastname: Montazeri
authors.forename: Nasim
authors.initials: N
authors.lastname: Maslehat
authors.forename: Sarah
authors.initials: S
authors.lastname: Elliott
authors.forename: Raul
authors.initials: R
authors.lastname: Fernandez-Gonzalez
authors.forename: Alexandra
authors.initials: A
authors.lastname: Calle
authors.forename: Alfonso
authors.initials: A
authors.lastname: Gutierrez-Adan
authors.forename: Alireza
authors.initials: A
authors.lastname: Fazeli
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D016207:Cytokines / Q000502:physiology; D004075:Diglycerides / Q000494:pharmacology; D010064:Embryo Implantation / Q000502:physiology*; D004717:Endometrium / Q000166:cytology / Q000502:physiology*; D005260:Female; D005298:Fertility / Q000502:physiology*; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D023421:Models, Animal; D008954:Models, Biological; D009842:Oligopeptides / Q000494:pharmacology; D010457:Peptidoglycan / Q000494:pharmacology; D011247:Pregnancy; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D051216:Toll-Like Receptor 6 / Q000502:physiology*; D014327:Trophoblasts / Q000166:cytology / Q000502:physiology
chemical_list: D016207:Cytokines; D004075:Diglycerides; C460864:FSL-1 lipoprotein, synthetic; D009842:Oligopeptides; D010457:Peptidoglycan; C493486:Tlr2 protein, mouse; C495369:Tlr6 protein, mouse; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6
keywords: endometrium; female infertility; implantation; toll-like receptors (TLR); trophoblast spheroids