Beta adrenergic blockade decreases the immunomodulatory effects of social disruption stress.

During physiological or psychological stress, catecholamines produced by the sympathetic nervous system (SNS) regulate the immune system. Previous studies report that the activation of ß-adrenergic receptors (ßARs) 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 ß-adrenergic antagonist propranolol. Pre-treatment with the ß-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 18h 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.

Repeated social defeat activates dendritic cells and enhances Toll-like receptor dependent cytokine secretion.

Stress hormones significantly impact dendritic cell (DC) activation and function, typically in a suppressive fashion. However, a social stressor termed social disruption (SDR) has been shown to induce an increase in inflammatory responses and a state of glucocorticoid resistance in splenic CD11b+ monocytes. These experiments were designed to determine the effects of SDR on DC activation, Toll-like receptor-induced cytokine secretion, and glucocorticoid sensitivity. Compared to cells obtained from control animals, splenic DCs from SDR mice displayed increased levels of MHC I, CD80, and CD44, indicative of an activated phenotype. In addition, DCs from SDR mice produced comparatively higher TNF-alpha, IL-6, and IL-10 in response to in vitro stimulation with LPS and CpG DNA. Increased amounts of TNF-alpha and IL-6 were also evident in SDR DC cultures stimulated with poly(I:C). Furthermore, as shown previously in CD11b+ monocytes, the CD11c+ DCs obtained from SDR mice were glucocorticoid resistant. Taken together, the data suggest that social stress, in the absence of any immune challenge, activates DCs, increases DC cytokine secretion in response to Toll-specific stimuli and renders DCs glucocorticoid resistant.