Involvement of TLR7 and TLR8 in conceptus development and establishment of pregnancy in sheep

Abstract

Toll-like receptors (TLRs) belong to the innate immune system and regulate inflammatory events that affect mammalian reproduction.In Study 1, we demonstrated that abundance of ovine TLR1-TLR9 mRNAs in the uterus differs due to reproductive status (TLR2, TLR3, TLR7, and TLR8) and the day of the estrous cycle and pregnancy (TLR1-TLR3, TLR5-TLR7, and TLR9). Expression of TLR7 and TLR8 proteins was localized primarily to uterine epithelia and stroma and regulated in a temporal manner. In Study 2, we determined that ovine conceptuses express TLR7 and TLR8 on all days studied and that expression of the envelope protein of ovine endogenous retrovirus (enJSRV-Env) declined in conceptus trophectoderm from Day 13 to Day 16 of pregnancy. In Study 3, loss-of-function experiments were conducted in vivo using morpholino antisense oligonucleotides (MAOs) injected into the uterine lumen to block synthesis of TLR7 and TLR8 proteins, individually and jointly. Conceptuses were recovered on Day 16 to assess their morphology. MAO-treated conceptuses were developmentally retarded, produced less interferon tau (IFNT), and had fewer binucleate cells (BNCs) compared with MAO-Controls. Moreover, expression of enJSRV-Env mRNA in MAO-TLR7 conceptuses was greater than that for MAO-Control and MAO-TLR8 conceptuses, but similar to MAO-TLR7/TLR8 conceptuses. Results of this study indicated differences in TLR1-TLR9 expression due to reproductive status and the day of the estrous cycle and pregnancy. TLR7 and TLR8 also influence development, enJSRV-Env abundance, secretion of IFNT, and formation of BNCs by conceptuses. These findings corroborate our hypothesis that TLR7 and TLR8 mediate pathways whereby enJSRV-Env regulates key peri-implantation events in conceptus development and differentiated functions of trophectoderm cells.

Early pregnancy affects expression of Toll-like receptor signaling members in ovine spleen

“…TLR7 participates in the maintenance of autoimmunity in the pathogenesis of experimental autoimmune encephalomyelitis in mice (Lalive et al, 2014). TLR7 is expressed in uterine epithelia and stroma, and conceptuses, which are involved in conceptus development and establishment of pregnancy during peri-implantation period in sheep (Ruiz-González et al, 2015). TLR7 expression is upregulated during early pregnancy, and TLR7 protein is particularly localized in endothelial cells of the CL in sheep (Atli et al, 2018).…”

Toll‐like receptor signaling is changed in ovine lymph node during early pregnancy

“…There is an upregulation of TLR5 in the endometrium from SCNT‐derived conceptuses comparing to that from natural mating, which indicates that TLR5 expression is aberrantly regulated in endometrium with SCNT‐derived conceptuses (Yoo et al., 2019). Expression of TLR5 mRNA is lower in primary first‐trimester trophoblasts and the trophoblast cell line BeWo in humans (Tangerås et al., 2014) and declined in the uterine endometria between days 16 and 20 of pregnancy in ewes (Ruiz‐González et al., 2015). TLR5 activation leads to a decline in trophoblast cells binding to endometrial cells in an in vitro model of human implantation, which is signaled through NF‐κB pathway (Caballero et al., 2013).…”

Identification of mRNAs related to endometrium function regulated by lncRNA CD36–005 in rat endometrial stromal cells

“…These results suggest us the dysregulated expression of TLR9 may be potentially involved in the pathogenesis of PCOS and its adverse endometrial outcomes. TRL-7 is crucial in the establishment and maintenance of pregnancy in sheep [ 56 ]. IL-8 participates in the pathogenesis of endometriosis by regulating ectopic endometrial cell proliferation, invasion, and adhesion [ 57 ].…”