Beta adrenergic blockade decreases the immunomodulatory effects of social disruption stress

Abstract

During physiological or psychological stress, catecholamines produced by the sympathetic nervous system (SNS) regulate the immune system. Previous studies report that the activation of β-adrenergic receptors (βARs) mediates the actions of catecholamines and increases pro-inflammatory cytokine production in a number of different cell types. The impact of the SNS on the immune modulation of social defeat has not been examined. The following studies were designed to determine whether SNS activation during social disruption stress (SDR) influences anxiety-like behavior as well as the activation, priming, and glucocorticoid resistance of splenocytes after social stress. CD-1 mice were exposed to one, three, or six cycles of SDR and HPLC analysis of the plasma and spleen revealed an increase in catecholamines. After six cycles of SDR the open field test was used to measure behaviors characteristic of anxiety and indicated that the social defeat induced increase in anxiety-like behavior was blocked by pre-treatment with the β-adrenergic antagonist propranolol. Pre-treatment with the β-adrenergic antagonist propranolol did not significantly alter corticosterone levels indicating no difference in activation of the hypothalamic–pituitary–adrenal axis. In addition to anxiety-like behavior the SDR induced splenomegaly and increase in plasma IL-6, TNFα, and MCP-1 were each reversed by pre-treatment with propranolol. Furthermore, flow cytometric analysis of cells from propranolol pretreated mice reduced the SDR-induced increase in the percentage of CD11b+ splenic macrophages and significantly decreased the expression of TLR2, TLR4, and CD86 on the surface of these cells. In addition, supernatants from 18 h LPS-stimulated ex vivo cultures of splenocytes from propranolol-treated SDR mice contained less IL-6. Likewise propranolol pre-treatment abrogated the glucocorticoid insensitivity of CD11b+ cells ex vivo when compared to splenocytes from SDR vehicle-treated mice. Together, this study demonstrates that the immune activation and priming effects of SDR result, in part, as a consequence of SNS activation.

Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis

“…Although mouse RSD and human low SES differ in many respects, these two chronic socials stressors share some general features in common, including periodic exposure to violence, persistent threat of physical harm, and chronically elevated catecholamine levels (47)(48)(49)56). The present results show that both of these chronic social stressors are also associated with similar increases in proinflammatory gene expression and monocyte differentiation.…”

“…Parallel expansion of the Ly-6c high monocyte population was observed in mice subject to a very different type of chronic social stress in RSD, which nevertheless shares with human low SES the involvement of elevated SNS catecholamine signaling (47)(48)(49)56). Bioinformatic analysis of differentially expressed genes suggested increased myelopoiesis as a potential mechanism for the selective up-regulation of immature proinflammatory monocytes.…”

Myeloid differentiation architecture of leukocyte transcriptome dynamics in perceived social isolation

“…Consistent with previous analyses of high-PSI humans (11,22) and socially stressed mice (7,(23)(24)(25)(26), circulating immune cells from high-PSI macaques also showed reduced glucocorticoid receptor (GR) functional activity, including blunted neutrophil redistribution response to endogenous diurnal variation in cortisol levels (Fig. 3D) and bioinformatic indications of down-regulated GR transcriptional activity and reciprocal upregulation of NF-κB (which is generally inhibited by GR signaling) (Fig.…”

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

“…Social disruption stress induces increased blood levels of proinflammatory cytokines and inflammatory monocytes, splenomegaly, increased monocyte trafficking to the brain, microglia activation in amygdala, hippocampus and prefrontal cortex, and hyper-anxiety (Hanke et al, 2012;Wohleb et al, 2011;Wohleb et al, 2013). Chronic exposure to social stress by an aggressive strain (chronic social defeat, CSD) induces increased blood levels of pro-inflammatory cytokines (TNF-, IL-6) and splenomegaly (Azzinnari et al, 2014;Savignac et al, 2011), and CSD mice exhibit increased social avoidance ( (Krishnan et al, 2007), see above), decreased active avoidance of footshock US (Azzinnari et al, 2014), and excessive CS fear expression (Yu et al, 2011).…”