Impacts of Immunometabolism on Male Reproduction

Abstract

The physiological process of male reproduction relies on the orchestration of neuroendocrine, immune, and energy metabolism. Spermatogenesis is controlled by the hypothalamic-pituitary-testicular (HPT) axis, which modulates the production of gonadal steroid hormones in the testes. The immune cells and cytokines in testes provide a protective microenvironment for the development and maturation of germ cells. The metabolic cellular responses and processes in testes provide energy production and biosynthetic precursors to regulate germ cell development and control testicular immunity and inflammation. The metabolism of immune cells is crucial for both inflammatory and anti-inflammatory responses, which supposes to affect the spermatogenesis in testes. In this review, the role of immunometabolism in male reproduction will be highlighted. Obesity, metabolic dysfunction, such as type 2 diabetes mellitus, are well documented to impact male fertility; thus, their impacts on the immune cells distributed in testes will also be discussed. Finally, the potential significance of the medicine targeting the specific metabolic intermediates or immune metabolism checkpoints to improve male reproduction will also be reassessed.

Keywords: hypothalamic-pituitary-testicular axis; immune cells; immune privilege; immunometabolism; male reproduction; metabolic reprogramming.

Figure 1

The hypothalamic-pituitary-testicular (HPT) axis and the testicular immune-privileged microenvironment. GnRH stimulates the release of pituitary gonadotropins, induces male reproductive function as well as affects cellular and humoral immune function. GnRH promotes the proliferation of immune cells and modifies cytokines production. Pituitary gonadotropins are involved in cellular and humoral immune development. Sex steroid hormones are secreted by the stimulation of LH that acts on Leydig cells in testis. Androgens and estrogens affect male reproductive function via modulation of the immune system and immune response. Various cell types present in the testicular interstitial space, including macrophages, DCs, T cells, NK cells, mast cells, and Leydig cells, providing a unique microenvironment for testicular functions. Androgens play crucial roles in maintaining the integrity of testicular immune-privileged microenvironment (solid arrow), while estrogens seem to play a stimulatory role in testicular immunoregulation which needs further investigations (dotted arrow).

Figure 2

A schematic diagram of the hypothetical metabolic homeostasis of immune cells in testes under physiological or inflammatory condition. In normal testes, immunologically tolerant cell phenotypes, comprising with macrophages (Mφ), immature DCs, Tregs, and regulatory NK cells, principally rely on OXPHOS and fatty acid oxidation pathway to fuel immunosuppressive functions and synthesis of anti-inflammatory cytokines (e.g., IL-10 and TGF-β). However, when testes suffer from pathogens or germ cell antigens attack, the number of macrophages and mast cells are markedly increased, and the location of these cells partially shift from the interstitium to the tubular compartment of infertile men testes. Furthermore, inflammatory phenotype cells such as infiltrating macrophages, mature DCs, effector T helper cells, and mast cells markedly show a metabolic shift towards the anaerobic glycolytic pathway to meet the rapid energy requirements and increased demands for synthesis of proinflammatory cytokine, like IL-6, NO and TNF-α. Then this cause ‘cytokine storm’ to disrupt the delicate equilibrium between immune privilege and tolerance, which trigger testes inflammation and impair normal spermatogenesis, followed by male infertility. Meanwhile, Sertoli cells also contribute to the immune-privileged status of mammalian testes, especially, maintain immature DCs, and inhibit effector T cells and NK cells via paracrine cytokines IDO and PDL-1. Similarly, Leydig cells play an immunoregulatory effect on maintenance of regulatory macrophage phenotype and inhibition of T cells immune responses through secreting lipid metabolites, such as testosterone, PGE₂ and PGI₂. Treg, regulatory T cells; DC, dendritic cell; Th, T helper cell; FAO, fatty acids oxidation; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid; PPP, pentose phosphate pathway; T, testosterone; PGE2 and PGI2, prostaglandins E2 and I2; IDO, indoleamine 2,3-dioxygenase; PDL-1, programmed death ligand-1; NO, nitric oxide; BV; blood vessel. +++, most abundant; ++, relatively abundant; +, present (28).