Intrathymic somatotropic circuitry: consequences upon thymus involution

Abstract

Growth hormone (GH) is a classic pituitary-derived hormone crucial to body growth and metabolism. In the pituitary gland, GH production is stimulated by GH-releasing hormone and inhibited by somatostatin. GH secretion can also be induced by other peptides, such as ghrelin, which interacts with receptors present in somatotropic cells. It is well established that GH acts directly on target cells or indirectly by stimulating the production of insulin-like growth factors (IGFs), particularly IGF-1. Notably, such somatotropic circuitry is also involved in the development and function of immune cells and organs, including the thymus. Interestingly, GH, IGF-1, ghrelin, and somatostatin are expressed in the thymus in the lymphoid and microenvironmental compartments, where they stimulate the secretion of soluble factors and extracellular matrix molecules involved in the general process of intrathymic T-cell development. Clinical trials in which GH was used to treat immunocompromised patients successfully recovered thymic function. Additionally, there is evidence that the reduction in the function of the somatotropic axis is associated with age-related thymus atrophy. Treatment with GH, IGF-1 or ghrelin can restore thymopoiesis of old animals, thus in keeping with a clinical study showing that treatment with GH, associated with metformin and dehydroepiandrosterone, could induce thymus regeneration in healthy aged individuals. In conclusion, the molecules of the somatotrophic axis can be envisioned as potential therapeutic targets for thymus regeneration in age-related or pathological thymus involution.

Keywords: ghrelin; growth hormone; insulin-like growth factor-1; somatostatin; thymic epithelial cells; thymocyte development; thymus; thymus involution.

Figure 1

Intrathymic somatotropic axis network. A thymic epithelial cell (TEC) is shown in the center of the figure, surrounded by three thymocytes and a blood vessel below. The somatotropic molecules reach the thymus through the bloodstream, thus characterizing an endocrine pathway. These hormones (identified by color) diffuse from the inside of the blood vessel into the organ and bind to their receptors on TEC and thymocytes. The ghrelin receptor signaling induces the intracellular production of GH, which in turn promotes the IGF-1 production. On the other hand, somatostatin inhibits the GH production. The figure also reveals the various possibilities of paracrine and autocrine action for each hormone, which is identified by the corresponding color. Filled colored arrows indicate well-established evidence for these hormone interactions, the dotted arrow in the somatostatin pathway indicates that the corresponding scientific evidence needs further studies. Asterisk in the GHS-R indicate that expression of this receptor has not yet been demonstrated in all TECs. Created with BioRender.com.

Figure 2

Potential rejuvenation of involuted thymus using GH and related peptides. Thymus involution is a physiological trait of aging that can also be triggered by pathogens. The consequence of this phenomenon is thymic atrophy, with impaired thymocyte maturation, increased cell death, increase in intrathymic adipocytes, and reduction in the export of naïve T lymphocyte to the periphery. Interestingly, there is evidence indicating an increase in the export of these cells in experimental Chagas disease (blue arrow). These changes were accompanied by a reduction in the GH, IGF-1, and ghrelin in the thymus. Importantly, some preclinical and clinical studies indicate that the treatment with these factors prevents and/or restore such atrophic thymus. Created with BioRender.com.