Mineralocorticoid receptor signaling reduces numbers of circulating human naïve T cells and increases their CD62L, CCR7, and CXCR4 expression.

The role of mineralocorticoid receptors (MRs) in human T-cell migration is not yet understood. We have recently shown that the MR antagonist spironolactone selectively increases the numbers of circulating naïve and central memory T cells during early sleep, which is the time period in the 24 h cycle hallmarked by predominant MR activation. To investigate whether this effect is specific to spironolactone's blockade of MRs and to study the underlying molecular mechanisms, healthy humans were given the selective MR-agonist fludrocortisone or placebo and numbers of eight T-cell subsets and their CD62L and CXCR4 expression were analyzed. Fludrocortisone selectively reduced counts of naïve CD4(+) , central memory CD4(+), and naïve CD8(+) T cells and increased CXCR4 expression on the naïve subsets. In complementing in vitro studies, fludrocortisone enhanced CXCR4 and CD62L expression, which was counteracted by spironolactone. Incubation of naïve T cells with spironolactone alone reduced CD62L and CCR7 expression. Our results indicate a regulatory influence of MR signaling on human T-cell migration and suggest a role for endogenous aldosterone in the redistribution of T-cell subsets to lymph nodes, involving CD62L, CCR7, and CXCR4. Facilitation of T-cell homing following sleep-dependent aldosterone release might thus essentially contribute to sleep's well-known role in supporting adaptive immunity.

Effects of an interleukin-1 receptor antagonist on human sleep, sleep-associated memory consolidation, and blood monocytes.

Pro-inflammatory cytokines like interleukin-1 beta (IL-1) are major players in the interaction between the immune system and the central nervous system. Various animal studies report a sleep-promoting effect of IL-1 leading to enhanced slow wave sleep (SWS). Moreover, this cytokine was shown to affect hippocampus-dependent memory. However, the role of IL-1 in human sleep and memory is not yet understood. We administered the synthetic IL-1 receptor antagonist anakinra (IL-1ra) in healthy humans (100mg, subcutaneously, before sleep; n=16) to investigate the role of IL-1 signaling in sleep regulation and sleep-dependent declarative memory consolidation. Inasmuch monocytes have been considered a model for central nervous microglia, we monitored cytokine production in classical and non-classical blood monocytes to gain clues about how central nervous effects of IL-1ra are conveyed. Contrary to our expectation, IL-1ra increased EEG slow wave activity during SWS and non-rapid eye movement (NonREM) sleep, indicating a deepening of sleep, while sleep-associated memory consolidation remained unchanged. Moreover, IL-1ra slightly increased prolactin and reduced cortisol levels during sleep. Production of IL-1 by classical monocytes was diminished after IL-1ra. The discrepancy to findings in animal studies might reflect species differences and underlines the importance of studying cytokine effects in humans.

Cortisol increases CXCR4 expression but does not affect CD62L and CCR7 levels on specific T cell subsets in humans.

Glucocorticoids are well known to affect T cell migration, leading to a redistribution of the cells from blood to the bone marrow, accompanied by a concurrent suppression of lymph node homing. Despite numerous studies in this context, with most of them employing synthetic glucocorticoids in nonphysiological doses, the mechanisms of this redistribution are not well understood. Here, we investigated in healthy men the impact of cortisol at physiological concentrations on the expression of different migration molecules on eight T cell subpopulations in vivo and in vitro. Hydrocortisone (cortisol, 22 mg) infused during nocturnal rest when endogenous cortisol levels are low, compared with placebo, differentially reduced numbers of T cell subsets, with naive CD4(+) and CD8(+) subsets exhibiting the strongest reduction. Hydrocortisone in vivo and in vitro increased CXCR4 expression, which presumably mediates the recruitment of T cells to the bone marrow. Expression of the lymph node homing receptor CD62L on total CD3(+) and CD8(+) T cells appeared reduced following hydrocortisone infusion. However, this was due to a selective extravasation of CD62L(+) T cell subsets, as hydrocortisone affected neither CD62L expression on a subpopulation level nor CD62L expression in vitro. Corresponding results in the opposite direction were observed after blocking of endogenous cortisol synthesis by metyrapone. CCR7, another lymph node homing receptor, was also unaffected by hydrocortisone in vitro. Thus, cortisol seems to redirect T cells to the bone marrow by upregulating their CXCR4 expression, whereas its inhibiting effect on T cell homing to lymph nodes is apparently regulated independently of the expression of classical homing receptors.

Signs of enhanced sleep and sleep-associated memory processing following the anti-inflammatory antibiotic minocycline in men.

Pro-inflammatory cytokines can promote sleep and neuronal processes underlying memory formation. However, this has mainly been revealed in animal studies. In this double-blind, placebo-controlled within-subject designed study, we examined how changes in the balance between pro- and anti-inflammatory signalling affect sleep and sleep-associated memory consolidation in humans. After learning declarative memory tasks (word pairs, texts) and a procedural memory task (finger tapping) in the evening, 21 healthy young men orally received either 200 mg of the anti-inflammatory antibiotic minocycline or placebo shortly before nocturnal sleep. Sleep was allowed between 23:00 and 07:00 h and recorded polysomnographically. Retrieval of memories was tested two days later. Because of outliers or missing data, final sample size was reduced to n = 14-19. Our data suggest that rather than weakening sleep as expected based on animal studies, the anti-inflammatory agent promoted sleep and memory consolidation. Specifically, minocycline increased slow-wave activity (0.68-4.0 Hz) during non-rapid eye movement sleep stage 2 and selectively enhanced episodic aspects in memory (i.e. memory for the temporal order of events in the texts). In combination with previous results, our findings indicate that, in humans, reducing pro-inflammatory signalling can act towards deepening non-rapid eye movement sleep and enhancing its memory forming efficacy.