Placental exosome-mediated Bta-miR-499-Lin28B/let-7 axis regulates inflammatory bias during early pregnancy

Abstract

Abnormal inflammatory bias in the maternal-fetal interface leads to reproductive failure in mammals. Placental exosomes are involved in maternal-fetal communication during pregnancy. However, whether the placenta or fetus is involved in regulating the balance of uterine local inflammation through exosomes remains unclear, and the mechanism must be further explored. Here we demonstrated that placenta-specific exosomes are abundant in the peripheral blood of dairy cows during early pregnancy and selectively load miRNAs, such as bta-miR-499. In vitro, placental exosome-derived bta-miR-499 inhibits the activation of NF-κB via the Lin28B/let-7 axis, thus repressing LPS-induced inflammation in bovine endometrial epithelial (BEND) cells. Subsequently, inhibition of mmu-miR-499 leads to an impaired balance of inflammation at the maternal-fetal interface in vivo, resulting in an increased risk of pregnancy failure due to placental loss and fetal growth restriction. Thus, our data demonstrate that placental exosomal miR-499 may be a critical immune regulator in the regulation of the inflammation balance at the maternal-fetal interface in the early gestation of dairy cows and other mammals.

Small RNA-seq analysis of extracellular vesicles from porcine uterine flushing fluids during peri-implantation

“…In these miRNAs, sssc-let-7a, ssc-let-7d-5p, ssc-let-7e, ssc-let-7f-5p, ssc-let-7g, ssc-let-7i-5p, ssc-miR-181c and ssc-miR-451 were cluster into Profile 6, while ssc-miR-21-5p, ssc-26a-5p and ssc-miR-181a were cluster into Profile5. A recent study demonstrated that let-7 family involved in the Lin28B/let-7 axis, which is the key regulatory mechanism of the immune inflammatory response during early pregnancy in cattle and the angiogenesis during the development of human malignances [49,50]. In addition, ssc-miR-181a and ssc-miR-181c may regulate embryo implantation by targeting SPP1 (adhesion molecule) in porcine endometrium [51].…”

Small RNA-seq analysis of exosomes from porcine uterine luminal fluid during peri-implantation

“…Moreover, let-7a, let-7c, let-7g and let-7i are involved the Lin28B/let-7 axis, which is the key regulatory mechanism of the immune inflammatory response during early pregnancy in cattle [35].…”

Exosomes as Messengers between Mother and Fetus in Pregnancy

“…In cattle, placenta-derived exosomes are abundant in the circulation of pregnant cows and exosome-derived miR-499 attenuated the expression of proinflammatory cytokines by inhibiting NF-κB signaling, thereby attenuating inflammatory responses and forming an immune-tolerant microenvironment in the uterus. Inhibition of miR-499 lead to inflammatory deregulation and increased risk of pregnancy failure [56].…”