Beta adrenergic blockade decreases the immunomodulatory effects of social disruption stress☆
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► The immunomodulatory effects of stress are abrogated by blocking the beta-adrenergic receptor on immune cells.
Introduction
Organisms survive by maintaining the complex dynamic equilibrium of homeostasis. When homeostasis is disturbed by endogenous or exogenous stressors, the sympathetic nervous system (SNS) and the hypothalamic–pituitary-adrenal axis (HPA) axis are activated. Under physiologic conditions, catecholamines and glucocorticoids (GCs) act as major regulators of fuel metabolism, heart rate, blood vessel tone, and thermogensis (Elenkov et al., 2000). The SNS is the largest component of the autonomic nervous system; it innervates all parts of the body including primary and secondary lymphoid organs. The splenic nerves are comprised of approximately 98% sympathetic nerve fibers and lack major cholinergic innervations (Klein et al., 1982, Madden et al., 1995). Noradrenergic innervation of lymphoid tissue is also regionally specific; for example, within the spleen, innervation occurs in dense zones of macrophages, T cells, and plasma cells. Products of the endocrine and nervous systems alter immune cell functioning in response to a stressor (Ader, 2006). The SNS contributes to the stress response through the release of catecholamines by sympathetic nerves in lymphoid tissue; catecholamines then mediate their effects on immune cells through the G-protein coupled adrenergic receptors. Moreover, norepinephrine and epinephrine are released from the adrenal medulla after SNS is activation during a stress response, in parallel to the release of glucocorticoids from the adrenal cortex. Norepinephrine is also released from sympathetic nerve fibers that heavily innervate lymphoid tissues. Norepinephrine and epinephrine mediate their effects on immune cells via stimulation of two major receptor subclasses: the alpha(α)- and the beta(β)-adrenergic receptors (ARs). When activated, this catecholaminergic system can provide the body with a needed ‘boost’ to deal with the immediate threat of the stressor. Hormones and neurotransmitters induced under stress bind specific receptors on immune cells and subsequently influence their activation and function. Recent studies indicate that activation of β2ARs in murine macrophages with the specific agonist, salmeterol, up-regulated IL-1β and IL-6 mRNA and protein levels resulting in an increased pro-inflammatory immune response (Tan et al., 2007). In addition, propranolol treatment 30 min prior to tailshock exposure attenuated plasma IL-1β and IL-6 levels (Johnson et al., 2005). Collectively, this indicates that stressor-induced activation of the HPA and SNS, which results in the release of glucocorticoids and catecholamines respectively, provides a significant link among the nervous, endocrine, and immune systems during the stress response in order to restore homeostasis (Chrousos, 1992, Madden, 2003).
Studies from our laboratory and others have demonstrated that social stress impacts peripheral physiologic responses as the host responds to new environmental demands caused by agonistic interactions (Bailey et al., 2006, Engler et al., 2005, Kinsey et al., 2007, Kinsey et al., 2008, Merlot et al., 2004, Quan et al., 2001). Social disruption stress (SDR), a model of repeated social defeat in mice, is associated with splenomegaly and the development of steroid insensitivity in splenic, CD11b+ and CD11c+ myeloid derived cell populations (Powell et al., 2009, Stark et al., 2001). Two hours of SDR induces a threefold increase in circulating corticosterone, yet the level of corticosterone returns to baseline by morning after each stress cycle (Sheridan et al., 2004). Six cycles of SDR results in the development of glucocorticoid (GC) resistance, where CD11b+ cells in the spleen become insensitive to GC-induced cell death (Stark et al., 2002). In addition, after LPS stimulation CD11b+ cells from SDR mice secrete more IL-6 than control cells (Stark et al., 2002), and CD11b+ macrophages from SDR mice have enhanced microbicidal activity when challenged with Escherichia coli (Bailey et al., 2007). Along with significant alterations in immune function, social defeat has been shown to cause lasting behavioral changes in rodents. For example, mice that observed a partner mouse as it received a series of electrical shocks displayed increased freezing during the shocks and also froze when placed back into the observing chamber the following day (Jeon et al., 2010). Also, mice that received one session of social defeat demonstrated increased immobility in the Porsolt forced swim test, a behavior associated with depression (Hebert et al., 1998). Similarly, repeated social defeat during SDR in mice increased anxiety-like behavior in the open field test, light/dark preference test, and the novel object test of neophobia, but had no effects on depressive-like behavior in the Porsolt forced swim test or the tail suspension test (Bailey et al., 2009b, Kinsey et al., 2007, Kinsey et al., 2008).
While the overall immune and behavioral outcomes of SDR have been reported (Avitsur et al., 2001, Kinsey et al., 2007, Meagher et al., 2007, Stark et al., 2001), the contribution of social stress-induced SNS activation on the development of anxiety-like behavior and altered monocyte/macrophage function is unknown. Therefore, the purpose of this study was to determine the extent of SNS activation induced by SDR and determine how this relates to the social stress-induced activation, priming and glucocorticoid resistance of CD11b+ cells. Here we showed that the SNS and HPA axis were activated by social defeat. In addition, blockade of the SNS response through β-adrenergic receptor antagonism did not significantly alter the HPA axis response, but did attenuate the SDR-induced splenomegaly, anxiety-like behavior and plasma IL-6 responses. Moreover, blockade of the β-adrenergic receptor abrogated the SDR enhanced expression of TLR2+, TLR4+, and CD86+ on the surface of splenocytes from socially defeated mice. β-adrenergic receptor antagonism reduced SDR macrophage activation and decreased the ex vivo response to LPS stimulation. It also restored the sensitivity of splenocytes to glucocorticoids ex vivo. Taken together, these data showed that activation of the SNS, and release of catecholamines, was responsible for the behavioral and peripheral physiological changes induced by exposure to repeated social stress.
Section snippets
Animals
Male CD1 mice at 6–8 weeks of age were obtained from Charles River Breeding Laboratories, Inc. (Hollister, CA) and allowed to acclimate to their surroundings for 7–10 days before initiation of any experimental procedures. Mice were housed three to five animals per cage and maintained at 21 °C under a 12 h light:12 h dark cycle with ad libitum access to water and rodent chow in an American Association of Accreditation of Laboratory Animal Care-accredited facility in Postle Hall at the Ohio State
SDR increased circulating and tissue catecholamines
Repeated social defeat increased the plasma levels of norepinephrine (Fig. 1A) and epinephrine (Fig. 1B) immediately after 1, 3 or 6 cycles of SDR. In addition, SDR also increased the concentration of norepinephrine in the spleen compared to controls (HCC) (Fig. 1C) while the levels of epinephrine in the spleen were not increased following SDR (data not shown). Plasma levels of both norepinephrine and epinephrine were increased immediately after 6 cycles of SDR (20 min) and returned to control
Discussion
The results of the current study indicate that activation of the SNS and catecholamine release during repeated social defeat are important mediators of the stress-induced anxiety-like behavior and modulation of splenocyte responses. First, the data showed there was a significant increase in circulating and tissue catecholamines in socially-defeated mice compared to controls. Second, β-adrenergic receptor antagonism blocked the SDR induced anxiety-like behavior. Third, pretreatment with the
Acknowledgments
The authors acknowledge the grateful assistance of Amy Hufnagle, Steve G. Kinsey, Jonathan P. Godbout and Tammy Kielian.
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This work was supported by the NIH National Institute for Mental Health RO1MH046801 and the National Institute for Dental and Cranial Research T32DE014320 to J.F.S.
- 1
Present Address: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.