Friday, May 9, 2025
5/9/2025
Oviduct Siglecs: Role in the Sperm Immune Response - Project Summary Sperm have a remarkable and still unexplained capacity to survive for extended periods in the oviduct, contrary to the strong innate immune response they elicit in the uterus. Following mating, when semen reaches the uterus, sperm interact with uterine epithelial cells to stimulate an inflammatory reaction. The release of pro-inflammatory cytokines induces a rapid infiltration of polymorphonuclear neutrophils (PMNs) into the uterus. PMNs then release neutrophil extracellular traps and phagocytose the majority of sperm. The few sperm that evade phagocytosis in the uterus move to the oviduct where, in stark contrast, they do not trigger a phagocytic response and can survive for extended periods ranging from hours to months, depending on the species. Indeed, in the isthmic region of the oviduct (nearest to the uterus), the presence of macrophages or neutrophils is rare. The oviduct demonstrates unique immunological privilege within the female reproductive system that enables remaining sperm to avoid elimination by phagocytes. The mechanisms underlying the different responses between the oviduct and the uterus are unknown. But the ability of sperm to survive and evade phagocytosis in the oviduct is critical for fertility. Sperm are coated with sialic acid-terminating glycans (sialoglycans) and changes in sialylation influence the ability of sperm to evade phagocytosis of uterine macrophages. Sialoglycans can interact with several proteins, including Siglecs (sialic acid-binding immunoglobulin-type lectins), the most abundant and best-known receptors for sialoglycans. There are many different Siglec proteins, found most commonly on leukocytes, and they are known for their ability to activate or inhibit the immune system, attract immune cells, and facilitate cell adhesion. However, Siglecs have also recently been localized to non-immune cells such as kidney and prostate epithelium and uterine and cervical epithelium. Using endpoint PCR, we discovered for the first time that 8 Siglecs are expressed in oviduct epithelium (porcine) and expression is biased towards Siglecs that inhibit the immune response. We also found that porcine sperm contain sialylated glycans that are high-preference Siglec ligands. These results led to our overall hypothesis that sperm sialoglycan binding to oviduct Siglecs alters cytokine production through Siglec-downstream signaling. This inhibits the innate immune response, allowing sperm to avoid immune rejection and phagocytosis during the storage period in the oviduct. To test this model using in vivo and in vitro studies, we will determine the role of Siglecs in the oviduct response to sperm by removing sperm sialic acid and blocking individual Siglecs to determine if oviduct cell gene expression, including the production of immune mediators, and chemotaxis is affected. We will determine if sperm interaction with oviduct cells is dependent on direct sialoglycan-Siglec binding. Finally, we will compare Siglec and intracellular signaling protein abundance and localization in the oviduct and uterus to investigate if that is responsible for the different innate immune responses of both organs to sperm. Collectively, these Aims will elucidate the role of oviduct Siglecs and sperm sialoglycans in suppressing the immune response in the oviduct, despite sperm being foreign cells that are largely phagocytosed in the uterus. The results may be used to enhance sperm lifespan in the oviduct and perhaps develop therapies for infertile females.
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