Intrathymic somatotropic circuitry: consequences upon thymus involution.

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.

Aberrant IL-17 Levels in Rodent Models of Autism Spectrum Disorder: A Systematic Review.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterised by stereotyped behaviours, specific interests, and impaired communication skills. Elevated levels of pro-inflammatory cytokines, such as interleukin-17A (IL-17A or IL-17), have been implicated as part of immune alterations that may contribute to this outcome. In this context, rodent models have helped elucidate the role of T-cell activation and IL-17 secretion in the pathogenesis of ASD. Regarding the preclinical findings, the data available is contradictory in offspring but not in the pregnant dams, pointing to IL-17 as one of the main drivers of altered behaviour in some models ASD, whilst there are no alterations described in IL-17 levels in others. To address this gap in the literature, a systematic review of altered IL-17 levels in rodent models of ASD was conducted. In total, 28 studies that explored IL-17 levels were included and observed that this cytokine was generally increased among the different models of ASD. The data compiled in this review can help the choice of animal models to study the role of cytokines in the development of ASD, seeking a parallel with immune alterations observed in individuals with this condition. Systematic Review Registration: PROSPERO, identifier CRD42022306558.

Neurotransmitters Modulate Intrathymic T-cell Development.

The existence of a crosstalk between the nervous and immune systems is well established. Neurotransmitters can be produced by immune cells, whereas cytokines can be secreted by cells of nervous tissues. Additionally, cells of both systems express the corresponding receptors. Herein, we discuss the thymus as a paradigm for studies on the neuroimmune network. The thymus is a primary lymphoid organ responsible for the maturation of T lymphocytes. Intrathymic T-cell development is mostly controlled by the thymic microenvironment, formed by thymic epithelial cells (TEC), dendritic cells, macrophages, and fibroblasts. Developing thymocytes and microenvironmental cells can be influenced by exogenous and endogenous stimuli; neurotransmitters are among the endogenous molecules. Norepinephrine is secreted at nerve endings in the thymus, but are also produced by thymic cells, being involved in controlling thymocyte death. Thymocytes and TEC express acetylcholine receptors, but the cognate neurotransmitter seems to be produced and released by lymphoid and microenvironmental cells, not by nerve endings. Evidence indicates that, among others, TECs also produce serotonin and dopamine, as well as somatostatin, substance P, vasoactive intestinal peptide (VIP) and the typical pituitary neurohormones, oxytocin and arg-vasopressin. Although functional data of these molecules in the thymus are scarce, they are likely involved in intrathymic T cell development, as exemplified by somatostatin, which inhibits thymocyte proliferation, differentiation, migration and cytokine production. Overall, intrathymic neuroimmune interactions include various neurotransmitters, most of them of non-neuronal origin, and that should be placed as further physiological players in the general process of T-cell development.

Experimental ischemia/reperfusion model impairs endocannabinoid signaling and Na+/K+ ATPase expression and activity in kidney proximal tubule cells.

LLC-PK1 cells, an immortalized epithelial cell line derived from pig renal proximal tubules, express all the major players of the endocannabinoid system (ECS) such as CB1, CB2 and TRPV1 receptors, as well as the main enzymes involved in the biosynthesis and degradation of the major endocannabinoids named 2-arachidonoylglycerol, 2-AG and anandamide, AEA. Here we investigated whether the damages caused by ischemic insults either in vitro using LLC-PK1 cells exposed to antimycin A (an inductor of ATP-depletion) or in vivo using Wistar rats in a classic renal ischemia and reperfusion (IR) protocol, lead to changes in AEA and 2-AG levels, as well as altered expression of genes from the main enzymes involved in the regulation of the ECS. Our data show that the mRNA levels of the CB1 receptor gene were downregulated, while the transcript levels of monoacylglycerol lipase (MAGL), the main 2-AG degradative enzyme, were upregulated in LLC-PK1 cells after IR model. Accordingly, IR was accompanied by a significant reduction in the levels of 2-AG and AEA, as well as of the two endocannabinoid related molecules, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in LLC-PK1 cells. In kidney cortex homogenates, only AEA levels were significantly decreased. In addition, we found that in both the in vitro and in vivo model IR caused a reduction in the expression and activity of the Na+/K+ ATPase. These changes were reversed by the CB1/CB2 agonist WIN55,212, in a CB1-receptor dependent manner in the LLC-PK1 IR model. In conclusion, the ECS and Na+/K+ ATPase are down-regulated following IR in LLC-PK1 cells and rat kidney. We suggest that CB1 agonists might represent a potential strategy to reverse the consequences of IR injury in kidney tissues.