Utero-Placental Immune Milieu During Normal and Aglepristone-Induced Parturition in the Dog

Abstract

Simple Summary The tolerance of the maternal immune system towards the embryo is essential for the success of pregnancy in all mammals. The uterine immunological milieu is modulated in a species-dependent manner, and pro-inflammatory responses are observed in the uterus during parturition in several species. An analogous situation was suggested for the dog. Nevertheless, details regarding immune signaling in the canine utero-placental compartments remain veiled. The present investigation of gene expression and immunolocalization of several immune-related factors revealed moderate utero-placental activity during mid-pregnancy (maintenance period). However, several immune factors were upregulated during parturition, suggesting an increased incidence of cells involved in tissue remodeling and/or immune regulation. The involvement of progesterone in these mechanisms was further assessed by using samples from mid-pregnant dogs treated with the progesterone receptor blocker, aglepristone. Similarities were observed in the expression pattern of several immune factors between natural and induced parturition, supporting the involvement of progesterone signaling in the modulation of the uterine immune milieu. This study provides the basis for further investigations regarding the immune regulation of parturition in the dog. Furthermore, differences observed between natural and induced parturition could be related to different placental maturation and/or functional characteristics of aglepristone, and might be of clinical relevance. Maternal immunotolerance is required for the maintenance of pregnancy, in sharp contrast with the uterine pro-inflammatory activity observed during parturition in several species. Correspondingly, in the dog, increased immune signaling at term has been suggested, but a deeper understanding of the uterine immune milieu is still missing. Thus, the availability of 30 immune-related factors was assessed in utero-placental samples collected during post-implantation (days 18-25 of pregnancy) and mid-gestation (days 35-40) stages, and at the time of prepartum luteolysis. Gene expression and/or protein localization studies were employed. Samples collected from antigestagen (aglepristone)-treated dogs were further analyzed. Progression of pregnancy was associated with the downregulation of IL1 beta and upregulation of IL10 (p < 0.05) at mid-gestation. When compared with mid-gestation, a higher availability of several factors was observed at term (e.g., CD206, CD4, TLR4). However, in contrast with natural parturition, MHCII, CD25, CCR7, TNF alpha, IDO1 and AIF1 were upregulated after aglepristone treatment (p < 0.05), but not TNFR1 or CCL13 (p > 0.05). Altogether, these results show an increased immune activity during canine parturition, involving, i.a., M2 macrophages, Treg and Th cells, with strong support for progesterone-mediated immunomodulation. Furthermore, differences between term and induced parturition/abortion could relate to differences in placental maturation towards parturition and/or functional traits of antigestagens.