Folliculo-stellate cells – Potential mediators of the inflammaging-induced hyperactivity of the hypothalamic–pituitary–adrenal axis in healthy elderly individuals

Abstract

Some evidence has suggested that, with age, the hypothalamic–pituitary–adrenal (HPA) axis becomes less resilient, leading to higher glucocorticoids nocturnal levels and a flattening of the circadian profiles. Such age-related changes in the activity of the HPA axis has overexposed the brain and peripheral organs to the effects of the glucocorticoids, increasing the morbidity and mortality rates of the elderly. Debate among scientists regarding the contributions of HPA axis age-related changes of impaired feedback regulation vs. direct overactivation persists. Supporters of impaired feedback regulation assumed that this effect might be the consequence of the hippocampal age-related neuronal loss and the reduction of the number of mineralocorticoid and glucocorticoid receptors. On the other hand, healthy elderly individuals are characterized by an increase of proinflammatory cytokines, including IL-1, IL-6, and TNF-α, and the development of a chronic low-grade inflammatory state, known as inflammaging. Cytokines central to inflammaging send signals to the brain, activate HPA axis, and, by increased cortisol secretion, down-regulate inflammaging in a process known as anti-inflammaging. Even as these cytokines act at the level of the hypothalamic paraventricular nucleus, they are hampered by the intact blood–brain barrier. Further, the corticotropes in the anterior pituitary do not express cytokine receptors, and the density of folliculo-stellate cells generally increases with age. Therefore, we assumed that folliculo-stellate cells were the target structures through which the elevated levels of cytokines, as a part of the inflammaging phenomenon, would cause the overactivation of the HPA axis in healthy elderly individuals. Folliculo-stellate cells are non-endocrine cells that were originally considered to act as supporting cells for the endocrine cells. Despite the fact that FS cells do not produce any of the established hormones of the anterior pituitary, they secrete paracrine agents that act locally to modulate pituitary responses to hypothalamic and peripheral signals. There is evidence of cytokines characteristically involved in inflammaging. For example, IL-1 and TNF-α are thought to stimulate folliculo-stellate cells to release various paracrine agents, including IL-6, IL-11, leukemia inhibitory factor, and macrophage migration inhibitory factor. Through different mechanisms, these agents induce ACTH release by corticotropes. Therefore, it can be concluded that folliculo-stellate cells may act as potent mediators of the age-related HPA axis hyperactivity induced by cytokines characteristic of the inflammaging phenomenon in healthy elderly individuals.