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

Abstract

Ageing is associated with a progressive decline in thymic cytoarchitecture followed by a less efficient T cell development and decreased emigration of naïve 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 β₂- and α₁-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 β₂- and α₁-AR-expressing thymic nonlymphoid cells and the α₁-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 α₁-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 naïve T cell output.

Catecholaminergic signalling through thymic nerve fibres, thymocytes and stromal cells is dependent on both circulating and locally synthesized glucocorticoids

“…However, the expression of α 1B ‐AR at both mRNA and protein levels per thymocyte and, most probably, α 1B ‐AR mRNA in thymic non‐lymphoid cells, was upregulated. In light of our previous data indicating that chronic blockade of α 1 ‐ARs increases thymic weight and cellularity (Leposavić et al 2011), the increased α 1B ‐AR expression on thymic cells and the elevated thymic NA level in KET‐treated rats were fully consistent with the decline in thymic weight and thymocyte number in these rats. The increase in α 1B ‐AR expression following removal of the local GC synthesis in rats deprived of adrenal GCs could be linked with the data showing that the gene for α 1B ‐AR contains a GC response element within its promoter region (Gao & Kunos, 1993) and that adrenalectomy increases α 1B ‐adrenoceptor mRNA levels in the rat hypothalamic paraventricular nucleus (Day et al 1999).…”

“…Considering the decrease in the thymic α 1B ‐AR mRNA expression in Adx rats in conjunction with the substantial increase in Nv of α 1B ‐AR‐ir cells, the reduced amount of α 1B ‐AR mRNA per thymocyte with unaltered Nv of α 1B ‐AR‐ir thymocytes and the markedly reduced Nv of α 1B ‐AR‐ir thymocytes compared with α 1B ‐AR‐ir non‐lymphoid cells, a diminished expression of α 1B ‐AR mRNA in non‐lymphoid cells from Adx rats may also be supposed. The subsets of TECs, macrophages and dendritic cells have been shown to express α 1B ‐ARs (Leposavić et al 2011).…”

“…Although the sympathetic nerve fibres are the main source of catecholamines (CAs) in rodent thymus (Felten et al 1985; Leposavić et al 1992; Elenkov et al 2000), their synthesis in thymocytes and thymic non‐lymphoid cells has also been demonstrated (Pilipović et al 2008). Moreover, it has been shown that CAs, acting on thymic lymphoid and non‐lymphoid cell β 2 ‐ and α 1B ‐adrenoceptors (ARs) provide fine‐tuning of thymocyte differentiation/maturation and, consequently, the maintenance of the peripheral T‐cell repertoire and self‐tolerance (reviewed by Leposavić et al 2011). Additionally, CAs released from thymic cells are also supposed to act as immunotransmitters, transferring information to nerve fibre endings (reviewed by Leposavić et al 2011).…”

“…Moreover, it has been shown that CAs, acting on thymic lymphoid and non‐lymphoid cell β 2 ‐ and α 1B ‐adrenoceptors (ARs) provide fine‐tuning of thymocyte differentiation/maturation and, consequently, the maintenance of the peripheral T‐cell repertoire and self‐tolerance (reviewed by Leposavić et al 2011). Additionally, CAs released from thymic cells are also supposed to act as immunotransmitters, transferring information to nerve fibre endings (reviewed by Leposavić et al 2011).…”

Regulation of Differentiation and Function of Helper T Cells by Lymphocyte-Derived Catecholamines via α₁- and β₂-Adrenoceptors

“…Norepinephrine hampers IL-12 and stimulates IL-10 production via β 2 - and α 2A -ARs in bone marrow-derived dendritic cells [32]. CAs derived from sympathetic nerves and produced locally by thymic cells provide a subtle tonic suppressive influence on T cell development acting via β 2 - and α 1 -ARs expressed on thymic nonlymphoid cells and thymocytes [33]. Previous work in our laboratory has also found that endogenous CA-induced lymphocyte apoptosis is mediated by α 1 - and β 2 -ARs [34].…”