Social regulation of leukocyte homeostasis: The role of glucocorticoid sensitivity

Abstract

Recent small-scale genomics analyses suggest that physiologic regulation of pro-inflammatory gene expression by endogenous glucocorticoids may be compromised in individuals who experience chronic social isolation. This could potentially contribute to the elevated prevalence of inflammation-related disease previously observed in social isolates. The present study assessed the relationship between leukocyte distributional sensitivity to glucocorticoid regulation and subjective social isolation in a large population-based sample of older adults. Initial analyses confirmed that circulating neutrophil percentages were elevated, and circulating lymphocyte and monocyte percentages were suppressed, in direct proportion to circulating cortisol levels. However, leukocyte distributional sensitivity to endogenous glucocorticoids was abrogated in individuals reporting either occasional or frequent experiences of subjective social isolation. This finding held in both nonparametric univariate analyses and in multivariate linear models controlling for a variety of biological, social, behavioral, and psychological confounders. The present results suggest that social factors may alter immune cell sensitivity to physiologic regulation by the hypothalamic-pituitary-adrenal axis in ways that could ultimately contribute to the increased physical health risks associated with social isolation.

Transcript origin analysis identifies antigen-presenting cells as primary targets of socially regulated gene expression in leukocytes

“…Future studies will need to confirm the present bioinformatic attributions of cell-specific transcriptional dynamics using physically isolated monocytes and dendritic cells. Nevertheless, the pattern of differential gene expression observed here is consistent with that emerging from other analyses of social adversity (5,7,46,47), including those using isolated monocytes (5). Finally, the teleological basis and health significance of these findings remain to be validated in future studies.…”

Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk

“…Our data are therefore based on the associations of cortisol with percentages of lymphocytes and neutrophils. We also use the ratio of neutrophils to lymphocytes (log 10 ) as an overall marker of the trafficking of these cells (5,24). Epinephrine and Norepinephrine.…”

“…Evidence for GCR in response to chronic stress has been found in parents of children with cancer (10), spouses of brain-cancer patients (11) and in persons reporting high levels of loneliness (5). Without sufficient glucocorticoid regulation, the duration and/or intensity of the inflammatory response increases, heightening risk for acute exacerbations such as occur in asthma and autoimmune diseases, as well as for the onset and progression of chronic inflammatory diseases such as CVD, and type II diabetes (12).…”

“…The lack of such studies is partly attributable to the as yet incomplete understanding of the effects of prolonged stress on the HPA in human subjects (4) and on determining which stress-induced changes in HPA play a downstream role in disease risk. The simple notion that chronic stress acts through the direct effects of elevated circulating cortisol is becoming less likely (5,6). What may matter more is how target tissues respond to cortisol, rather than levels of the hormone per se.…”

“…22, 23). Cole and his colleagues (5,24) showed that this association can be used to indirectly assess GCR. The logic of the measure is that there is a strong physiologic correlation between cortisol levels and the number of circulating leukocytes only if leukocyte glucocorticoid receptors are sensitive (i.e., signaling cells to redistribute).…”