Innate immune system for a crosstalk of sperm-egg-uterine epithelium towards fertility: Toll-like receptor 2 as a physiological sensor.

In cattle, innate immunity plays a key role in the crosstalk between sperm, egg, and uterus, which is critical for the success of assisted reproductive technologies (ARTs). This review highlights Toll-like receptor 2 (TLR2) as a physiological sensor that modulates these interactions. Following artificial insemination, TLR2-mediated sperm-uterine interactions initiate a controlled immune response. This response is essential for clearing excess sperm and preparing the endometrium for embryo implantation. Similar to sperm, the egg yolk-based semen extender could also activate endometrial TLR2, leading to a mild uterine inflammation. This spotlights a dual role for TLR2: a sensor for sperm and a responder to external stimuli from ART. Beyond these artificial factors, microbial components either disrupt or support uterine health via TLR2. Peptidoglycan (PGN) from pathogenic bacteria like Staphylococcus aureus induces inflammation and negatively impacts fertility. In contrast, PGN from beneficial bacteria like Lacticaseibacillus and Lactobacillus suppresses TLR2-mediated inflammation, promoting uterine homeostasis. Beyond the uterus, sperm-TLR2 activation improves fertilization and embryo development during in vitro embryo production. TLR2 is also functionally expressed in early bovine embryos, where its activation enhances embryo developmental competence. Collectively, TLR2 is a physiological sensor during early reproductive events in cattle, and its activation could be a strong approach to improve ARTs.