Of vessels and cells: the spatial organization of the epididymal immune system

Abstract

Background: One third of infertility cases in couples worldwide has an exclusive male origin and immune disorders, essentially due to repetitive infections, are emerging an cause of male infertility. As the place of sperm maturation, epididymis must be preserved from excessive immune responses that may arise following infections of the male genital tract. At the same time, epididymis must set and maintain a tolerogenic environment in order not to destroy sperm cells that enter the tissue at puberty, long after the immune system has been taught to recognize self pathogens. The immune cells that populate the epididymis have raised growing interest over the last thirty years but they may be not sufficient to understand the immune balance existing in this organ, between immune response to pathogens and tolerance to spermatozoa. Indeed, immune cells are the most motile cells in the organism and need blood and lymphatic vessels to traffic between lymphoid organs and sites of infection to induce efficient responses. Objectives: To review the literature on the blood and lymphatic vessels, and on the immune cells present at steady state in the rodent epididymis (rat and mouse). Materials and methods: PubMed database was searched for studies reporting on the spatial organization of the rodent epididymal vasculature and immune cell types at steady state. This search was combined with recent findings from our team. Results: At steady state, the rodent epididymis presents with dense blood and lymphatic networks, and a large panel of immune cells distributed across the interstitum and epithelium along the organ. Conclusions: The immune system of the rodent epididymis is highly organized. Exploring its functions, especially in an infectious context, is the essential coming step before any transposition to human.

An atlas of cell types in the mouse epididymis and vas deferens

“…The presence of both blood and lymph vessels was expected from prior studies ( Guiton et al, 2019 ; endothelial cells are not further considered here. As for immune cells, the immune populations identified by scRNA-Seq are generally concordant with previous histological and FACS-based analyses which show that macrophages, dendritic cells, and infiltrating lymphocytes represent the predominant groups of immune cells involved in the blood-epididymis barrier ( Da Silva and Barton, 2016 ; Nashan et al, 1989 ; Serre and Robaire, 1999 ; Sun and Flickinger, 1979 ; Voisin et al, 2018 ).…”

Granulocyte-macrophage colony stimulating factor (GM-CSF) is fully expressed in the genital tract, seminal plasma and spermatozoa of male pigs

“…The epididymis also showed both active and higher glycosylated forms of GM-CSF, but maintaining the same WB densitometry picture, with the active form dominating, being conspicuous in caput and corpus compared to cauda epididymides. GM-CSF stimulates the proliferation and maturation of granulocytes and macrophages, cells present in the epithelium and epididymal interstitial tissue and even passing to the epididymal lumen 29 probably to maintain an appropriate immunological environment for spermatozoa and also for protecting them from potential pathogens 30 . The distribution of GM-CSF we documented, follows the distribution seen for macrophages in rodents 30 – 32 , suggesting there might also be a putative greater presence of macrophages in these epididymal regions in boars, a matter we have not specifically mapped in the present study.…”

“…GM-CSF stimulates the proliferation and maturation of granulocytes and macrophages, cells present in the epithelium and epididymal interstitial tissue and even passing to the epididymal lumen 29 probably to maintain an appropriate immunological environment for spermatozoa and also for protecting them from potential pathogens 30 . The distribution of GM-CSF we documented, follows the distribution seen for macrophages in rodents 30 – 32 , suggesting there might also be a putative greater presence of macrophages in these epididymal regions in boars, a matter we have not specifically mapped in the present study. A matter to consider, is that our relative distribution of both active form (low glycosylation) and highly glycosylated forms of epididymal GM-CSF, considered hereby the contribution of vesicles and residual cytoplasmic bodies 33 .…”

The Immune Characteristics of the Epididymis and the Immune Pathway of the Epididymitis Caused by Different Pathogens

“…In contrast to the immunologically privileged testis, the epididymis does not support prolonged allogeneic graft survival (85). Furthermore, epithelial tight junctions of the rodent epididymis may not be as effective as those of the blood-testis barrier, and direct interactions between intra-epithelial immune cells and either sperm antigens or ascending pathogens is possible (71). Therefore, the epididymis is more prone to inflammation and autoimmune responses than the testis.…”

“…Defensins are not only important regulatory molecules in the biological immune system but are also important antimicrobial peptides with direct bactericidal functions ( 70 ). Multiple beta-defensins have been found in the epididymis of humans and mice with region-specific expression patterns, showing bacteria-killing activity and the promotion of sperm motility ( 71 , 72 ).…”