The male reproductive immune system plays a pivotal role in safeguarding sperm from immune attacks and preventing the incursion of foreign pathogens. Nucleotide-binding and oligomerization domain-like receptors (NOD-like receptors, NLRs) family protein domain containing 3 (NLRP3) is a cytoplasmic sensor binding to the inflammasome and critically involved in inducing innate immunity in the testes. It also has a substantial impact on male reproductive immunity, which is closely associated with male infertility stemming from disorders related to the male reproductive immune system. This review introduces the distinct characteristics of the NLR family, elucidates the activation pathways and factors of NLRP3 inflammasomes, and discusses how they participate in male reproductive immune diseases such as bacterial orchitis, autoimmune orchitis, varicocele, and epididymitis. In bacterial orchitis, elevated levels of NLRP3 inflammasomes exacerbate the testicular inflammatory injury and lead to decreased testosterone, thus contributing to male infertility. In autoimmune orchitis, the NLRP3 inflammasomes inhibit testosterone synthesis by decreasing the expression of cytochrome P450, thereby impacting male reproductive function. Therefore, targeting NLRP3 could offer novel immunological strategies for the clinical treatment of male infertility.

The reproductive axis of male mammals implies a coordinated interaction of its three components: a population of gonadotropin-releasing hormone (GnRH)—producing neurons of the hypothalamus, gonadotropic cells of the adenohypophysis, and most distally located testes that produce male sex hormone (testosterone) and germ cells (spermatozoa). It is generally believed that for the accurate and constant realization of reproductive function, the testes must be isolated from the internal environment of the whole organism with the help of a hematotesticular barrier. The internal immune system of the testes is primarily represented by testicular macrophages. They are located primarily in the peritubular space and provide the physical organization of peritubular myoid cells into niche-like clusters that can form an environment conducive to the differentiation of spermatogonia A1 in sperm cells. The development of this complex system occurs in mammals over a long period and is determined by the timely synchronization of all its parts. Maternal immune activation (MIA) is associated with the powerful production of proinflammatory cytokines in the mother’s body and further in the placenta and fetal region. Many of these cytokines have a pleiotropic effect and act as morphogenetic factors. Thus, cytokines can influence the development of testes even in the prenatal period. The review is focused on the effect of MIA on testicular development during prenatal state and on the holistic nature of the development of the reproductive axis of mammals on the example of laboratory rodents. Laboratory rodents (especially mice) are often used to develop models of the development of certain human systems and are the generally accepted standard for the introduction of these models into medical practice.

The control of the immune system, neuroendocrine system, and energy metabolism is essential for the physiological process of male reproduction. The hypothalamic-pituitary-testicular (HPT) axis regulates the generation of gonadal steroid hormones in the testes, which in turn controls spermatogenesis. For the growth and maturation of germ cells, the immune cells and cytokines in the testes offer a safe microenvironment. The cellular reactions and metabolic activities in the testes produce energy and biosynthetic precursors that control the growth of germ cells, as well as testicular immunology and inflammation. Both inflammatory and anti-inflammatory responses depend on immune cell metabolism, which is thought to influence testicular spermatogenesis. The significance of immunometabolism in male reproduction will be underlined in this review.

Testicular sperm maturation is critical for establishing male fertility. Spermatozoa undergo remodeling of sperm proteins and changes in lipid and ribonucleic acid composition during transport in the epididymal ducts, which play an important role in sperm maturation. The anatomy, epithelial cell types, physiological functions, and epigenetic inheritance of the epididymis are explored, and recent findings in epididymal research are analyzed. Suggesting possible directions for future research on the epididymis. Using the keywords “epididymis”, “sperm”, and “sperm maturation”, a search of the epididymis was performed through databases and official websites of journals related to reproduction. The epididymis was searched in databases and on the official websites of journals related to reproduction. This review introduces the characteristics of the epididymis, as well as the biological functions of cell types such as principal cells, clear cells, and basal cells, providing a detailed description of the overall physiological functions of the epididymis. It highlights current research hotspots in the field of epididymis, including single-cell analysis, epigenetics, and extracellular vesicles, aiming to offer a comprehensive understanding for beginners. The review emphasizes the importance of the epididymis, its impact on sperm maturation and subsequent embryo development, and how it advances research on epididymal diseases while providing new directions for the study and treatment strategies of infertility.

Epididymitis or epididymo-orchitis is a common urological condition in males characterized by scrotal pain, swelling, and potential urinary symptoms. Although antibiotics can eliminate the causative pathogens, persistent inflammation may compromise spermatogenesis and steroidogenesis. The testis, an immune-privileged organ, possesses a specialized immune microenvironment that shields germ cells (GCs) from autoimmune attacks and orchestrates immune defenses against pathogens. This review focuses on the complex interplay between immune cells, including macrophages, dendritic cells (DCs), mast cells (MCs), and T cell subsets, in the testis. The roles of these immune cells in infection-induced orchitis were deliberated upon, emphasizing their involvement in inflammation and immune tolerance. Furthermore, the implications of testicular fibrosis and its effect on male infertility are discussed, emphasizing the role of MCs in tissue remodeling. The objective of this review is to expand comprehension of male reproductive health and foster the identification of potential therapeutic targets for epididymo-orchitis.