Immune Regulation of Seminal Plasma on the Endometrial Microenvironment: Physiological and Pathological Conditions

Abstract

Seminal plasma (SP) accounts for more than 90% of semen volume. It induces inflammation, regulates immune tolerance, and facilitates embryonic development and implantation in the female reproductive tract. In the physiological state, SP promotes endometrial decidualization and causes changes in immune cells such as macrophages, natural killer cells, regulatory T cells, and dendritic cells. This leads to the secretion of cytokines and chemokines and also results in the alteration of miRNA profiles and the expression of genes related to endometrial tolerance and angiogenesis. Together, these changes modulate the endometrial immune microenvironment and contribute to implantation and pregnancy. However, in pathological situations, abnormal alterations in SP due to advanced age or poor diet in men can interfere with a woman's immune adaptation to pregnancy, negatively affecting embryo implantation and even the health of the offspring. Uterine pathologies such as endometriosis and endometritis can cause the endometrium to respond negatively to SP, which can further contribute to pathological progress and interfere with conception. The research on the mechanism of SP in the endometrium is conducive to the development of new targets for intervention to improve reproductive outcomes and may also provide new ideas for semen-assisted treatment of clinical infertility.

Keywords: cytokines; embryo implantation; endometrium; immune cell; immune tolerance; pregnancy; seminal plasma.

Figure 1

Source and main components of seminal plasma (SP). The SP mainly comes from the seminal vesicle, prostate, epididymis, and bulbourethral gland. It includes water, saccharides, lipids, proteins, ions, nucleic acids, polyamines, peptides, chemokines, cytokines, vesicles, organic acids, inorganic acids, etc.

Figure 2

The endometrial microenvironment responds to the immune regulation of seminal plasma (SP). Key signaling factors in SP, including transforming growth factor (TGF)-β, prostaglandins (PGs), and interleukin (IL)-8, interact with endometrial epithelial cells and endometrial stromal cells (ESCs). They can induce the secretion of pro-inflammatory cytokines and chemokines and promote ESC decidualization and the changes in the number and phenotype of natural killer (NK) cells and macrophages. Antigens in the SP can be presented by dendritic cells (DCs), driving the activation and expansion of regulatory T cells (Tregs), which recognize and respond to paternal antigens. Changes in miRNAs in uterine tissue caused by SP also contribute to regulating DC and Treg function. Cytokines and proteases secreted by immune cells are conducive to the establishment of maternal immune tolerance to the embryo. Together, these changes promote embryo implantation. However, advanced age or poor diet in men can lead to abnormal changes in SP, which interfere with women’s immune adaptation to pregnancy and negatively affect embryo implantation.