Abstract
Leydig cells (Lc), located in the interstitial space of the testis between seminiferous tubules, produce 95% of testosterone in male individuals, which is pivotal for male sexual differentiation, spermatogenesis, and maintenance of the male secondary sex characteristics. Lc are prone to senescence in aging testes, resulting in compromised androgen synthesis capability upon aging. However, little is known about whether Lc undergo senescence in a chronic inflammatory environment. To investigate this question, mouse models of experimental autoimmune orchitis (EAO) were used, and Lc were analyzed by high throughput scRNA-Seq. Data were screened and analyzed by correlating signaling pathways with senescence, apoptosis, androgen synthesis, and cytokine/chemokine signaling pathways. EAO did induce Lc senescence, and Lc senescence in turn antagonized androgen synthesis. Based on the correlation screening of pathways inducing Lc senescence, a plethora of pathways were found to play potential roles in triggering Lc senescence during EAO, among which the Arf6 and angiopoietin receptor pathways were highly correlated with senescence signature. Notably, complement and interstitial fibrosis activated by EAO worsened Lc senescence and strongly antagonized androgen synthesis. Furthermore, most proinflammatory cytokines enhanced both senescence and apoptosis in Lc and spermatogonia (Sg) during EAO, and proinflammatory cytokine antagonism of the glutathione metabolism pathway may be key in inducing cellular senescence during EAO.
Highlights
Leydig cells (Lc) senescence in aging testes leads to reduced serum testosterone levels and hypogonadism, affecting male fertility in 2%–3% of aging men (1)
Orchitis led to extensive changes in gene expression (Figure 1B), especially in Sg and Sd7-Sd9 spermatids, which were located either adjacent to the interstitium or faced the lumens of seminiferous tubules, respectively, making these cells more vulnerable to be affected by immune factors
Orchitis altered the expression of key genes from senescence and apoptosis pathways in some cell clusters, such as an increase in senescence markers Cdkn1b and Cdkn1c in Lc cells and an increase in apoptosis markers Trp53/p53 and Pten in Sg cells (Figure 1G)
Summary
Lc senescence in aging testes leads to reduced serum testosterone levels and hypogonadism, affecting male fertility in 2%–3% of aging men (1). The prevalent viewpoint is that the factors contributing to Lc senescence during aging are intrinsic factors, such as the reduced steroidogenic capacity, lowered response to luteinizing hormone (LH) stimulation, reduced cholesterol import, reduced cholesterol synthesis, and compromised transport to mitochondria in aging Lc (2, 3). The age-related decline of Lc function involves extrinsic factors such as chronic inflammation (11), which has been largely neglected in earlier studies. Local inflammation in the testes activates macrophages at the site to produce reactive oxygen species (ROS) such as hydrogen peroxide, which can perturb Lc function in the interstitium (13). Low serum androgen levels in aged men usually correlates with elevated levels of circulating proinflammatory cytokines (14, 15)
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