Varicocele-Mediated Male Infertility: From the Perspective of Testicular Immunity and Inflammation

Abstract

BackgroundVaricocele (VC) is present in 35 - 40% of men with infertility. However, current surgical and antioxidant treatments are not completely effective. In addition to oxidative stress, it is likely that other factors such as testicular immune microenvironment disorder contribute to irreversible testicular. Evidence suggests that VC is associated with anti-sperm antibodies (ASAs), spermatogenesis and testosterone secretion abnormalities, and testicular cytokine production. Moreover, inhibition of inflammation can alleviate VC-mediated pathogenesis. The normal function of the testis depends on its immune tolerance mechanism. Testicular immune regulation is complex, and many infectious or non-infectious diseases may damage this precision system.ResultsThe testicular immune microenvironment is composed of common immune cells and other cells involved in testicular immunity. The former includes testicular macrophages, T cells, dendritic cells (DCs), and mast cells, whereas the latter include Leydig cells and Sertoli cells (SCs). In animal models and in patients with VC, most studies have revealed an abnormal increase in the levels of ASAs and pro-inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha in the seminal plasma, testicular tissue, and even peripheral blood. It is also involved in the activation of potential inflammatory pathways, such as the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing (NLRP)-3 pathway. Finally, the development of VC-mediated infertility (VMI) may be facilitated by abnormal permeability of proteins, such as claudin-11, that constitute the blood-testis barrier (BTB).ConclusionsThe testicular immune response, including the production of ASAs and inflammatory factors, activation of inflammatory pathways, and destruction of the BTB may be involved in the pathogenesis of VMI it is necessary to further explore how patient outcomes can be improved through immunotherapy.

Long noncoding RNAs regulated spermatogenesis in varicocele‐induced spermatogenic dysfunction

“…'regulation of immune effector process,' 'leukocyte apoptotic pro- Many studies have shown that inflammatory mechanisms play important roles in VC. 31,32 IL-1α and IL-1β have been reported to be increased in the VC model. 33,34 Camargo et al found that IL-1, IL-18 and caspase-1 decreased in semen after varicocelectomy by ELISAs.…”

“…Many studies have shown that inflammatory mechanisms play important roles in VC 31,32 . IL‐1α and IL‐1β have been reported to be increased in the VC model 33,34 .…”

Single-Cell Transcriptomics-Based Study of Transcriptional Regulatory Features in the Non-Obstructive Azoospermia Testis

“…tMΦ produce several growth and differentiation factors for LC development ( Heinrich and DeFalco, 2020 ). In addition to testicular immunosuppression, tMΦ also locally regulate LC steroidogenesis ( Fang et al, 2021 ). Previous studies have delineated the phenotype of tMΦ in the normal testis, and tMΦ have been implicated in the development of azoospermia ( Hussein et al, 2005 ; Duan et al, 2011 ).…”

Resveratrol and Immune Cells: A Link to Improve Human Health

“…These cells include macrophages, T cells, DCs, and mast cells associated with Leydig cells and Sertoli cells (SCs). Several studies have shown an overproduction of pro-inflammatory cytokines dependent on alterations of this microenvironment as in the case of varicocele [124]. The anti-inflammatory action of RSV could inhibit this cytokine hypersecretion, counteracting infertility.…”