Complementing Testicular Immune Regulation: The Relationship between Sertoli Cells, Complement, and the Immune Response

Abstract

Sertoli cells within the testis are instrumental in providing an environment for spermatogenesis and protecting the developing germ cells from detrimental immune responses which could affect fertility. Though these immune responses consist of many immune processes, this review focuses on the understudied complement system. Complement consists of 50+ proteins including regulatory proteins, immune receptors, and a cascade of proteolytic cleavages resulting in target cell destruction. In the testis, Sertoli cells protect the germ cells from autoimmune destruction by creating an immunoregulatory environment. Most studies on Sertoli cells and complement have been conducted in transplantation models, which are effective in studying immune regulation during robust rejection responses. In grafts, Sertoli cells survive activated complement, have decreased deposition of complement fragments, and express many complement inhibitors. Moreover, the grafts have delayed infiltration of immune cells and contain increased infiltration of immunosuppressive regulatory T cells as compared to rejecting grafts. Additionally, anti-sperm antibodies and lymphocyte infiltration have been detected in up to 50% and 30% of infertile testes, respectively. This review seeks to provide an updated overview of the complement system, describe its relationship with immune cells, and explain how Sertoli cells may regulate complement in immunoprotection. Identifying the mechanism Sertoli cells use to protect themselves and germ cells against complement and immune destruction is relevant for male reproduction, autoimmunity, and transplantation.

Complements from the Male Reproductive Tract: A Scoping Review

“…A significant limitation in the study of complement in the male reproductive tract, and in general, is that mouse models do not translate well to humans, particularly regarding CD46 [100,101]. In rodents, CD46 is only expressed on the acrosome of sperm and in Sertoli cells [37]. In humans, CD46 is expressed ubiquitously, and it is particularly important in T cell metabolism, clonal expansion, and survival [101].…”

“…Cells important in these testicular functions include Sertoli cells, Leydig cells, peritubular myoid cells, and testicular macrophages. Of these, complement expression has been confirmed in Sertoli cells, Leydig cells, macrophages, and germ cells [3,18,19,23,[37][38][39] (Figure 3, Table 1). Germ cells will be discussed later with seminal plasma.…”

“…The Dufour lab has identified the most detailed milieu of complement components expressed by Sertoli cells as of the writing of this review: 25 cascade factors, 21 inhibitors, and 2 receptors, for a total of 48 complement-related proteins (Figure 3, Table 1) [18]. These proteins have been described in detail by Washburn et al [18] and extensively reviewed [37]. In brief, expression of nearly all complement cascade factors was detected in mouse, pig, and human Sertoli cells [18,47].…”

“…They also express the complement regulators C1INH, C1QBP, CD35, CD46, CD55, CD59, CLU, Factor H, Factor I, PTX3, SMAP1, and SMAP2 [39], which inhibit complement at key points to prevent amplification and complement-mediated inflammation. Furthermore, macrophages express many complement receptors (CD35, CR3, CR4, CRIg, C3aR, C5aR1, and C5aR2), which initiate specific events in the macrophage, including activation of the macrophage, the enhancement of phagocytosis, macrophage differentiation (M1 or M2), chemotaxis and extravasation, and the suppression of macrophage function ( [59][60][61], reviewed in [37]).…”

Oxidative Stress, Cytotoxic and Inflammatory Effects of Azoles Combinatorial Mixtures in Sertoli TM4 Cells

“…SCs have a key role in maintaining functional spermatogenesis, providing nutritional and structural support for germ cells. They are also essential for the testis because of their production of follicle-stimulating hormone receptor (FSHR) and the androgen-binding protein (ABP) [ 34 ], and crucial for their direct implication in the blood–testis barrier (BTB) and in the release of various immunomodulatory factors [ 35 ]. In this context, a high level of proinflammatory cytokines produced by SCs, especially tumor necrosis factor-alpha (TNF-α), affects BTB functions, thereby leading to the impairment of spermatogenesis [ 36 , 37 , 38 , 39 , 40 ].…”