Cytokines in Male Fertility and Reproductive Pathologies: Immunoregulation and Beyond

Abstract

Germline development in vivo is dependent on the environment formed by somatic cells and the differentiation cues they provide; hence, the impact of local factors is highly relevant to the production of sperm. Knowledge of how somatic and germline cells interact is central to achieving biomedical goals relating to restoring, preserving or restricting fertility in humans. This review discusses the growing understanding of how cytokines contribute to testicular function and maintenance of male reproductive health, and to the pathologies associated with their abnormal activity in this organ. Here we consider both cytokines that signal through JAKs and are regulated by SOCS, and those utilizing other pathways, such as the MAP kinases and SMADs. The importance of cytokines in the establishment and maintenance of the testis as an immune-privilege site are described. Current research relating to the involvement of immune cells in testis development and disease is highlighted. This includes new data relating to testicular cancer which reinforce the understanding that tumorigenic cells shape their microenvironment through cytokine actions. Clinical implications in pathologies relating to local inflammation and to immunotherapies are discussed.

Differential gene regulation in selected lines for high and low sperm production in male guppies

“…Therefore, the selection for higher production of sperm was concurrent to higher expression of genes, such as interleukins, that control immune cell functions in the testis. These genes are also expressed by nonimmune cells, playing a key role in the regulation of spermatogonial and spermatocyte development (Loveland et al, 2017). Interleukin‐2 has proliferative activity in T cells and is mediated by the activation of the phosphoinositide 3‐kinase (PI3K) which was also upregulated in the pathway of the HS line.…”

“…For this reason, sperm are protected from the host immune response thanks to a complex multitude of factors both physical and immunological that make the testes an immunologically privileged organ (O'Bryan & Hedger, 2009). The physical blood–testis barrier, that separates post‐meiotic germ cells from immature cells in peri‐ and inter‐tubular spaces, impedes the recognition of the post‐meiotic cells as foreign (Loveland et al, 2017). Testicular somatic cells, and especially the Sertoli cell, play an important role in the regulation of this property (O'Bryan & Hedger, 2009).…”

Immune regulatory molecules as modifiers of semen and fertility: A review

“…Cytokines have many pathophysiological functions in testis and seminal plasma that are mediated in a coordinated manner (Loveland et al, ). For example, during infection, an increase in PTGE might impede the cell‐mediated response to spermatozoa, while the overall cytokine production during the humoral response is enhanced to fight against the infection (Kelly, ).…”

Microenvironmental signals govern the cellular identity of testicular macrophages

“…The term immune privilege, as applied to the testis, originated from studies on prolonged allograft (e.g., parathyroid) and xenograft survival, placed experimentally in the testicular interstitium . This implies that, apart from specific systemic tolerance against germ cell Ags, more general local mechanisms must exist that create a unique immunosuppressed microenvironment, providing protection for a wide array of different Ags …”

“…13 This implies that, apart from specific systemic tolerance against germ cell Ags, more general local mechanisms must exist that create a unique immunosuppressed microenvironment, providing protection for a wide array of different Ags. [14][15][16][17][18] Emerging evidence indicates that the testicular somatic cells contribute to a microenvironment that affects the TM phenotype. Putative players include the SC as a source for numerous factors with immunoregulatory functions, such as TGF-, activin A, CCL2, and IDO, the LC, with androgens, and possibly the TM themselves, with 25-hydroxycholesterol (25HC).…”