Immunological uterine response to pig embryos before and during implantation

Abstract

The establishment of a successful pregnancy can only occur through a concerted functioning of the entire female reproductive system, allowing for fertilization, subsequent embryo development and implantation of the conceptus. In this context, the uterine immunological responses responsible for rejection or tolerance of the conceptus are of critical importance. The aim of the present review is to summarize our current knowledge about those cellular and molecular immunological events occurring at the uterine level during pre-implantation and implantation stages of pregnancy in the pig. Advancing our understanding of the immune mechanisms involved in the success or failure of pregnancy will provide cues to develop novel strategies augmenting endometrial receptivity, finally increasing the efficiency of assisted reproductive technologies in pigs.

Keywords: allogenic; embryo; hemiallogenic; immune tolerance; pig; pregnancy.

FIGURE 1

Schematic overview of some immunological events taking place at the uterine level to achieve a successful pregnancy in pigs. Post‐Mating Inflammatory Cascade: During the first days after mating, increased expression of pro‐inflammatory factors, such as cytokines (i.e., GM‐CSF) and other factors (i.e., MCP‐1 and COX‐2) together with an important increase in leukocyte infiltration (neutrophils, macrophages, dendritic cells and T lymphocytes) occurs. A pro‐inflammatory environment is predominant in this period with two main functions, namely, the elimination of bacteria and excess sperm debris and, more importantly, priming of the maternal immune system with paternal antigens. Pre‐Implantation Period: During this stage, the neutrophils disappear, but macrophages and dendritic cells remain, acting as antigen‐presenting cells and they temporarily activate the immune system toward immunotolerance, therefore tolerating free‐floating conceptuses before their attachment to the endometrial surface. Implantation Period: During the early implantation period (Day 12), E2 secreted by the elongating conceptuses is the signal for maternal pregnancy recognition in pigs. Conceptus‐secreted E2 maintains adequate P4 levels for optimal endometrial receptivity and modulates the expression of endometrial genes related to cell growth, adhesion mechanisms, PG synthesis and immune regulation, all of which are essential for conceptus development. During the mid‐implantation stages (Day 18), a pro‐inflammatory status at the cellular and molecular levels is established, and vascular changes and angiogenesis allowing embryo implantation are evident. Finally, during the late implantation period, the immune environment shifts again to an anti‐inflammatory status that allows for placental development and is maintained until the peripartum stages. COX‐2, cyclo‐oxygenase‐2; E2, estrogens; GM‐CSF, granulocyte‐macrophage colony stimulation factor; MCP‐1, monocyte chemoattractant protein‐1; P4, progesterone; PG, prostaglandin

FIGURE 2

Percentage of anti‐ to pro‐inflammatory cytokine ratios shifted to anti‐inflammatory status in the endometrium of blastocyst bearing (BB) and uninseminated cyclic (U‐IC) sows. (a) Among 25 ratios showing significant differences between BB and U‐IC sows, 15 (60%) shifted toward anti‐inflammatory status in BB sows and 10 in U‐IC sows (48%). (b) Within the 25 ratios showing significant differences between BB and U‐IC sows, 12 shifted toward anti‐inflammatory status in both groups of sows, and among them, 10 (83.3%) were higher in endometrial samples from BB sows. (Modified from Parrilla et al., 2020)