Glucocorticoids, master modulators of the thymic catecholaminergic system?

There is evidence that the major mediators of stress, i.e., catecholamines and glucocorticoids, play an important role in modulating thymopoiesis and consequently immune responses. Furthermore, there are data suggesting that glucocorticoids influence catecholamine action. Therefore, to assess the putative relevance of glucocorticoid-catecholamine interplay in the modulation of thymopoiesis we analyzed thymocyte differentiation/maturation in non-adrenalectomized and andrenalectomized rats subjected to treatment with propranolol (0.4 mg.100 g body weight(-1).day(-1)) for 4 days. The effects of beta-adrenoceptor blockade on thymopoiesis in non-adrenalectomized rats differed not only quantitatively but also qualitatively from those in adrenalectomized rats. In adrenalectomized rats, besides a more efficient thymopoiesis [judged by a more pronounced increase in the relative proportion of the most mature single-positive TCR alpha beta(high) thymocytes as revealed by two-way ANOVA; for CD4(+)CD8(-)F (1,20) = 10.92, P lt 0.01; for CD4(-)CD8(+)F (1,20) = 7.47, P lt 0.05], a skewed thymocyte maturation towards the CD4(-)CD8(+) phenotype, and consequently a diminished CD4(+)CD8(-)/CD4(-)CD8(+) mature TCR alpha beta(high) thymocyte ratio (3.41 +/- 0.21 in non-adrenalectomized rats vs 2.90 +/- 0.31 in adrenalectomized rats, P lt 0.05) were found. Therefore, we assumed that catecholaminergic modulation of thymopoiesis exhibits a substantial degree of glucocorticoid-dependent plasticity. Given that glucocorticoids, apart from catecholamine synthesis, influence adrenoceptor expression, we also hypothesized that the lack of adrenal glucocorticoids affected not only beta-adrenoceptor- but also alpha-adrenoceptor-mediated modulation of thymopoiesis

Characterization of thymocyte phenotypic alterations induced by long-lasting beta-adrenoceptor blockade in vivo and its effects on thymocyte proliferation and apoptosis

Adult male Wistar rats were subjected to propranolol (P, 0.40 mg/100 g/day) or saline (S) administration (controls) over 14 days. The expression of major differentiation molecules on thymocytes and Thy-1 (CD90) molecules, which are shown to adjust thymocyte sensitivity to TCR alpha beta signaling, was studied. In addition, the sensitivity of thymocytes to induction of apoptosis and concanavalin A (Con A) signaling was estimated. The thymocytes from P-treated (PT) rats exhibited an increased sensitivity to induction of apoptosis, as well as to Con A stimulation. Furthermore, P treatment produced changes in the distribution of thymocyte subsets suggesting that more cells passed positive selection and further differentiated into mature CD4+ or CD8+ single positive (SP) TCR alpha beta(high) cells. These changes may, at least partly, be related to the markedly increased density of Thy-1 surface expression on TCR alpha beta(low) thymocytes from these rats. The increased frequency of cells expressing the CD4+25+ phenotype, which has been shown to be characteristic for regulatory cells in the thymus, may also indicate alterations in thymocyte selection following P treatment. Inasmuch as positive and negative selections play an important role in continuously reshaping the T-cell repertoire and maintaining tolerance, the hereby presented study suggests that pharmacological manipulations with beta-AR signaling, or chemically evoked alterations in catecholamine release, may interfere with the regulation of thymocyte selection, and consequently with the immune response

Role of gonadal hormones in programming developmental changes in thymopoietic efficiency and sexual diergism in thymopoiesis

There is a growing body of evidence indicating the important role of the neonatal steroid milieu in programming sexually diergic changes in thymopoietic efficiency, which in rodents occur around puberty and lead to a substantial phenotypic and functional remodeling of the peripheral T-cell compartment. This in turn leads to an alteration in the susceptibility to infection and various immunologically mediated pathologies. Our laboratory has explored interdependence in the programming and development of the hypothalamo-pituitary-gonadal axis and thymus using experimental model of neonatal androgenization. We have outlined critical points in the complex process of T-cell development depending on neonatal androgen imprinting and the peripheral outcome of these changes and have pointed to underlying mechanisms. Our research has particularly contributed to an understanding of the putative role of changes in catecholamine-mediated communications in the thymopoietic alterations in adult neonatally androgenized rats

Age-Associated Remodeling of Neural and Nonneural Thymic Catecholaminergic Network Affects Thymopoietic Productivity

Ageing is associated with a progressive decline in thymic cytoarchitecture followed by a less efficient T cell development and decreased emigration of naive T cells to the periphery. These thymic changes are linked to increased morbidity and mortality from infectious, malignant and autoimmune diseases in old age. Therefore, it is of paramount importance to understand the thymic homeostatic processes across the life span, as well as to identify factors and elucidate mechanisms driving or contributing to the thymic involution. Catecholamines (CAs) derived from sympathetic nerves and produced locally by thymic cells represent an important component of the thymic microenvironment. In young rats, they provide a subtle tonic suppressive influence on T cell development acting via beta(2)- and alpha(1)-adrenoceptors (ARs) expressed on thymic nonlymphoid cells and thymocytes. In the face of thymic involution, a progressive increase in the thymic noradrenaline level, reflecting a rise in the density of noradrenergic nerve fibers and CA-synthesizing cells, occurs. In addition, the density of beta(2)- and alpha(1)-AR-expressing thymic nonlymphoid cells and the alpha(1)-AR thymocyte surface density also exhibit a pronounced increase with age. The data obtained from studies investigating effects of AR blockade on T cell development indicated that age-related changes in CA-mediated thymic communications, certainly those involving alpha(1)-ARs, may contribute to diminished thymopoietic efficiency in the elderly. Having in mind thymic plasticity in the course of ageing, and broadening possibilities for pharmacological modulation of CA signaling, we here present and discuss the progress in research related to a role of CAs in thymic homeostasis and age-related decay in the thymic naive T cell output. Copyright (C) 2011 S. Karger AG, Base

End-point effector stress mediators in neuroimmune interactions: their role in immune system homeostasis and autoimmune pathology

Much evidence has identified a direct anatomical and functional link between the brain and the immune system, with glucocorticoids (GCs), catecholamines (CAs), and neuropeptide Y (NPY) as its end-point mediators. This suggests the important role of these mediators in immune system homeostasis and the pathogenesis of inflammatory autoimmune diseases. However, although it is clear that these mediators can modulate lymphocyte maturation and the activity of distinct immune cell types, their putative role in the pathogenesis of autoimmune disease is not yet completely understood. We have contributed to this field by discovering the influence of CAs and GCs on fine-tuning thymocyte negative selection and, in particular, by pointing to the putative CA-mediated mechanisms underlying this influence. Furthermore, we have shown that CAs are implicated in the regulation of regulatory T-cell development in the thymus. Moreover, our investigations related to macrophage biology emphasize the complex interaction between GCs, CAs and NPY in the modulation of macrophage functions and their putative significance for the pathogenesis of autoimmune inflammatory diseases