Social stress induces glucocorticoid resistance in macrophages

Abstract

Stress-induced levels of plasma glucocorticoid hormones are known to modulate leukocyte function. These experiments examined the effects of a social stressor on the responsiveness of peripheral immune cells. Male mice experienced six evening cycles of social disruption (SDR), in which an aggressive male intruder was placed into their home cage for 2 h. Although circulating corticosterone was elevated in SDR mice, they had enlarged spleens and increased numbers of splenic leukocytes. Splenocytes from SDR and control mice were cultured with lipopolysaccharide and corticosterone. Cells from SDR mice exhibited decreased sensitivity to the antiproliferative effects of corticosterone, suggesting that the peripheral immune cells were resistant to glucocorticoids. In addition, SDR cells produced more interleukin (IL)-6. To determine which cell population was affected, we used antibody-labeled magnetic beads to deplete splenocyte suspensions of B cells or macrophages. Depletion of macrophages from SDR cultures, but not depletion of B cells, abolished both the corticosterone resistance and enhanced IL-6 secretion. These findings demonstrate that a psychosocial stressor induced glucocorticoid resistance in mouse splenic macrophages.

A Functional Genomic Fingerprint of Chronic Stress in Humans: Blunted Glucocorticoid and Increased NF-κB Signaling

“…These findings converge with evidence from studies of rodents, which experimentally manipulate exposure to stressors, and find that it diminishes sensitivity to glucocorticoidmediated signaling, both in the immune and nervous systems (19,44). They also converge with a recent microarray profile of socially isolated individuals, which documented a similar pattern of diminished GR-and heightened NF-κB-dependent transcription (29).…”

“…Although the design precludes inferences about the direction of causal relationships, it is difficult to conceive of plausible reverse-directionality explanations for the findings. Moreover, covariance analyses ruled out a variety of potential demographic, behavioral, and biomedical confounders, and the results converge with experimental studies in animals, wherein the causal influence of stressors on sensitivity to glucocorticoid signaling has been established (19,44). Nonetheless, the findings need to be considered preliminary until they have been substantiated with larger samples, more rigorous prospective designs, additional functional indicators of glucocorticoid sensitivity, and assessments of other hormonal response systems (e.g., the sympathetic nervous system).…”

“…One hypothesis attempting to reconcile these apparently conflicting observations postulates that chronic stressors bring about functional resistance to cortisol-mediated signaling (14,(16)(17)(18). Initial support for this proposition has emerged in a series of studies where chronic stressors have been shown to diminish the capacity of glucocorticoids to suppress ex vivo inflammatory cytokine production (14,17,19,20).…”

“…Support for this account has accrued in studies of humans and animals (14,17,19,20), where chronic stressors have been shown to diminish the capacity of glucocorticoids to suppress endotoxin-stimulated cytokine production. While these findings provide encouraging support for the glucocorticoid-resistance hypothesis, it is difficult to draw definitive conclusions from them, because they rely on ex vivo methods, synthetic analogues of cortisol, and/or high doses of endotoxin to activate monocytes.…”

Interleukin-1 receptor type 1-deficient mice fail to develop social stress-associated glucocorticoid resistance in the spleen

“…Previous studies have demonstrated that repeated social stress in mice is associated with decreased GC sensitivity of immune cells and excessive inflammation Engler et al, 2005;Johnson et al, 2004;Merlot et al, 2004;Sonoda et al, 2005;Stark et al, 2001). For example, lipopolysaccharide (LPS)-stimulated splenocytes from mice that repeatedly experienced acute encounters with an aggressive conspecific exhibited considerably higher cell survival in the presence of corticosterone (CORT) and showed greatly enhanced production of pro-inflammatory cytokines compared to splenocyte cultures from non-stressed controls (Avitsur et al, 2005Merlot et al, 2004;Stark et al, 2001). The decrease in splenic GC responsiveness was only observed after stimulation with LPS whereas unstimulated cells did not differ in their ex vivo response to CORT.…”