Social Disruption Stress Research Articles

Neonatal experience interacts with adult social stress to alter acute and chronic Theiler’s virus infection

Previous research has shown that neonatal handling has prolonged protective effects associated with stress resilience and aging, yet little is known about its effect on stress-induced modulation of infectious disease. We have previously demonstrated that social disruption stress exacerbates the acute and chronic phases of the disease when applied prior to Theiler's virus infection (PRE-SDR) whereas it attenuates disease severity when applied concurrently with infection (CON-SDR). Here, we asked whether neonatal handling would protect adult mice from the detrimental effects of PRE-SDR and attenuate the protective effects of CON-SDR on Theiler's virus infection. As expected, handling alone decreased IL-6 and corticosterone levels, protected the non-stressed adult mice from motor impairment throughout infection and reduced antibodies to myelin components (PLP, MBP) during the autoimmune phase of disease. In contrast, neonatal handling X PRE/CON-SDR elevated IL-6 and reduced corticosterone as well as increased motor impairment during the acute phase of the infection. Neonatal handling X PRE/CON-SDR continued to exacerbate motor impairment during the chronic phase, whereas only neonatal handling X PRE-SDR increased in antibodies to PLP, MOG, MBP and TMEV. Together, these results imply that while handling reduced the severity of later Theiler's virus infection in non-stressed mice, brief handling may not be protective when paired with later social stress.

Exposure of scented candle combustion aerosol on stress-induced cadiopulmonary injury

Background: Social stress may induce cardiopulmonary injury by disrupting the body’s homeostasis. Scented candles have been used to relieve stress. However, numerous air pollutants produced from burning scented candles may cause poor health outcomes. Aims: To investigate effects of scented candle combustion products exposure on social stress-induced cardiopulmonary injury in mice. Methods: Mice with social disruption stress (SDR) were exposed to combustion products of 3% lavender scented candles (4.5 h/d, 5 d/wk) in an exposure chamber for different time course (4 or 8 wk). Results: Exposure to combustion products of scented candle failed to reduce serum corticosterone level in SDR-treated mice in 4 and 8 weeks. Exposure to combustion products of scented candle time-dependently enhanced SDR-induced pulmonary edema, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, interleukin (IL)-1beta levels, and nuclear factor (NF)-kB activity in lung. Further, combustion products of scented candle time-dependently increased lactic dehydrogenase, creatine phosphokinase, and heart type creatine kinase isoenzyme levels in serum, hypoxia-inducible factor (HIF)-1alpha, and B-type natriuretic peptide levels in SDR-treated mice. Conclusions: Exposure to combustion products of 3% lavender scented candle may time-dependently exacerbated social stress-induced cardiopulmonary injury.

Impact of psychosocial stress on airway inflammation and its mechanism in a murine model of allergic asthma

Background It has already been recognized that psychosocial stress evokes asthma exacerbation; however, the mechanism of how stress gets inside the body is not clear. This study aimed to observe the impact of psychosocial stress on airway inflammation and its mechanism in the ovalbumin-induced asthmatic mice combined with social disruption stress. Methods Thirty-six male BALB/c mice were randomly divided into: control group, asthma group (ovalbumin-induced), asthma plus social disruption stress group (SDR), and SDR group. The open field video tracking system was used to assess animal behaviors. The invasive pulmonary resistance (RL) and dynamic lung compliance (cdyn) test system from Buxco was applied to detect pulmonary function. The enzyme-linked immunosorbent assay (ELISA) was utilized to determine OVA-IgE, T-helper type 2 (Th2) cytokines (IL-4, IL-5, IL-13) and corticosterone in mouse serum, the Th2 cytokines (IL-4, IL-5, IL-13, IL-6, TNF-α) in bronchoalveolar lavage fluid (BALF), and IL-6 and TNF-α levels in the supernatant of splenocytes cultured in vitro. Hematoxylin-eosin (H&E) staining was used to assess airway inflammation in lung histology. The cell count kit-8 assay (CCK-8) was applied to evaluate the inhibitory effect of corticosterone on splenocyte proliferation induced by lipopolysaccharide (LPS). Real time-PCR and Western blotting were utilized to determine glucocorticoid receptor (GR) mRNA and GR protein expression in lungs. Results The open field test showed that combined allergen exposure and repeated stress significantly shortened the time the mice spent in the center of the open field (P <0.01), increased ambulatory activity (P <0.01) and the count of fecal boli (P <0.01), but deceased vertical activity (P <0.01). Results from pulmonary function demonstrated that airway hyperresponsiveness (AHR) was enhanced by psychosocial stress compared with allergy exposure alone. The ELISA results showed that cytokines in serum and BALF were significantly increased (P <0.05). Moreover, the lung histology showed that infiltrated inflammatory cells were significantly increased in the asthma-SDR group compared with the asthma group (P <0.05). Interestingly, serum corticosterone was remarkably raised by psychosocial stress (P <0.05). In addition, the inhibitory effect of corticosterone on IL-6 and TNF-α in LPS-stimulated splenocyte cultures in vitro was diminished in the asthma-SDR group compared to the asthma group. The CCK-8 test revealed that the inhibition effect of corticosterone on splenocyte proliferation induced by LPS was significantly impaired in the SDR and asthma-SDR groups, while no significant effect was observed in the control and asthma groups. Furthermore, expression of GR mRNA and GR protein were significantly reduced in the lung tissues of the asthma-SDR group (P <0.05). Conclusions Social disruption stress can promote anxiety behavior, activate the hypothalamic-pituitary-adrenal (HPA) axis, increase AHR and inflammation, and also impair glucocorticoid sensitivity and its function in a murine model of asthma. The down-regulation of GR expression induced by social disruption stress is in part associated with glucocorticoid insensitivity, which leads to asthma exacerbation.

Chronic social stress impairs virus specific adaptive immunity during acute Theiler's virus infection

Prior exposure to social disruption (SDR) stress exacerbates Theiler's murine encephalomyelitis virus (TMEV) infection, a model of multiple sclerosis. Here we examined the impact of SDR on T cell responses to TMEV infection in SJL mice. SDR impaired viral clearance and exacerbated acute disease. Moreover, TMEV infection alone increased CD4 and CD8 mRNA expression in brain and spleen while SDR impaired this response. SDR decreased both CD4+ and CD8+ virus-specific T cells in CNS, but not spleen. These findings suggest that SDR-induced suppression of virus-specific T cell responses contributes to impairments in viral clearance and exacerbation of acute disease.

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 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 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.

Stressor-Induced Increase in Microbicidal Activity of Splenic Macrophages Is Dependent upon Peroxynitrite Production

Exposing mice to a social stressor called social disruption (SDR) that involves repeated social defeat during intermale aggression results in increased circulating cytokines, such as interleukin-1α (IL-1α) and IL-1β, and increased reactivity of splenic CD11b(+) macrophages to inflammatory stimuli. For example, upon lipopolysaccharide stimulation, macrophages from stressor-exposed mice produce higher levels of cytokines than do cells from nonstressed controls. Moreover, the SDR stressor enhances the ability of these macrophages to kill Escherichia coli both in vitro and in vivo, through a Toll-like receptor 4-dependent mechanism. The present study tested the hypothesis that stressor-enhanced bacterial killing is due to increases in the production of peroxynitrite. Male mice were exposed to the SDR stressor or were left undisturbed. Upon stimulation with E. coli, splenic macrophages from SDR-exposed mice expressed significantly increased levels of inducible nitric oxide synthase mRNA and produced higher levels of peroxynitrite. Blocking the production of peroxynitrite abrogated the SDR-induced increase in microbicidal activity. Studies in IL-1 receptor type 1 knockout mice indicated that the increased microbicidal activity and peroxynitrite production was dependent upon IL-1 signaling. These data confirm and extend the importance of IL-1 signaling for stressor-induced immunopotentiation; the finding that inhibiting superoxide or nitric oxide production inhibits both peroxynitrite production and killing of E. coli demonstrates that peroxynitrite mediates the stressor-induced increase in bacterial killing.

Psychosocial stress and inflammation in cancer

Stress-induced immune dysregulation results in significant health consequences for immune related disorders including viral infections, chronic autoimmune disease, and tumor growth and metastasis. In this mini-review we discuss the sympathetic, neuroendocrine and immunologic mechanisms by which psychosocial stress can impact cancer biology. Both human and animal studies have shown the sympathetic and neuroendocrine responses to psychosocial stress significantly impacts cancer, in part, through regulation of inflammatory mediators. Psychosocial stressors stimulate neuroendocrine, sympathetic, and immune responses that result in the activation of the hypothalamic-pituitary-adrenal (HPA)-axis, sympathetic nervous system (SNS), and the subsequent regulation of inflammatory responses by immune cells. Social disruption (SDR) stress, a murine model of psychosocial stress and repeated social defeat, provides a novel and powerful tool to probe the mechanisms leading to stress-induced alterations in inflammation, tumor growth, progression, and metastasis. In this review, we will focus on SDR as an important model of psychosocial stress in understanding neural-immune mechanisms in cancer.

Stress and the anti-influenza immune response: Repeated social defeat augments clonal expansion of CD8+T cells during primary influenza A viral infection

Social disruption stress (SDR) prior to primary influenza A virus (IAV) infection augments memory to IAV re-challenge in a T cell-specific manner. However, the effect of SDR on the primary anti-viral immune response has not been elucidated. In this study, SDR-infected (INF) mice terminated viral gene expression earlier and mounted an enhanced pulmonary IAV-specific CD8+T cell response versus controls. Additionally, SDR-INF mice had a more pro-inflammatory lung profile prior to and during infection and an attenuated corticosterone response. These data demonstrate neuroendocrine modification of the lung microenvironment and increased antigen-specific T cell activation, clonal expansion and viral control in stress-exposed mice.

Social disruption stress increases IL-6 levels and accelerates atherosclerosis in ApoE−/− mice

IntroductionWe have previously shown that different forms of stress have distinctive effects on atherogenesis in mice. We showed that social stress increase atherosclerosis in ApoE−/− mice, while more physical forms of stress do not. Here we evaluated the effect of social disruption (SDR) stress on atherogenesis and evaluated cytokine release after SDR-stress and five more physical stressors. MethodsMale ApoE−/− mice were exposed to SDR-stress during 12weeks, and atherosclerotic plaque area was assessed in aorta, aortic root and innominate artery. Further, male C57BL/6 mice were exposed to SDR-stress or five physical stressors, and cytokine and corticosterone levels were analyzed in plasma/serum samples immediately after stress. ResultsWe found a correlation between the level of SDR-stress and atherosclerotic plaque area in aorta and a numerical increased plaque area in aortic root. SDR stress did not affect histological features of plaque composition. However, SDR-stress increased levels of corticosterone, IL-6 and CXCL1. Plasma corticosterone increased for all five physical stressors, but IL-6 and CXCL1 only increased in the group exposed to restraint combined with rat odor. ConclusionsThese findings suggest that SDR-stress is indeed atherogenic, in contrast to our previous results using the physical stressors. A possible explanation to this difference is that SDR-stress, but not physical stressors, leads to release of the pro-inflammatory cytokines IL-6 and CXCL1.

The intestinal microbiota are necessary for stressor-induced enhancement of splenic macrophage microbicidal activity

The indigenous microbiota impact mucosal, as well as systemic, immune responses, but whether the microbiota are involved in stressor-induced immunomodulation has not been thoroughly tested. A well characterized murine stressor, called social disruption (SDR), was used to study whether the microbiota are involved in stressor-induced enhancement of macrophage reactivity. Exposure to the SDR Stressor enhanced the ability of splenic macrophages to produce microbicidal mediators (e.g., inducible nitric oxide synthase (iNOS), superoxide anion, and peroxynitrite) and to kill target Escherichia coli. Exposure to the SDR Stressor also increased cytokine production by LPS-stimulated splenic macrophages. These effects, however, were impacted by the microbiota. Microbicidal activity and cytokine mRNA in splenic macrophages from Swiss Webster germfree mice that lack any commensal microbiota were not enhanced by exposure to the SDR Stressor. However, when germfree mice were conventionalized by colonizing them with microbiota from CD1 conventional donor mice, exposure to the SDR Stressor again increased microbicidal activity and cytokine mRNA. In follow-up experiments, immunocompetent conventional CD1 mice were treated with a cocktail of antibiotics to disrupt the intestinal microbiota. While exposure to the SDR Stressor-enhanced splenic macrophage microbicidal activity and cytokine production in vehicle-treated mice, treatment with antibiotics attenuated the SDR Stressor-induced increases in splenic macrophage reactivity. Treatment with antibiotics also prevented the stressor-induced increase in circulating levels of bacterial peptidoglycan, suggesting that translocation of microbiota-derived peptidoglycan into the body primes the innate immune system for enhanced activity. This study demonstrates that the microbiota play a crucial role in stressor-induced immunoenhancement.

Social disruption induced priming of CNS inflammatory response to Theiler's virus is dependent upon stress induced IL-6 release

Chronic social disruption stress (SDR) exacerbates acute and chronic phase Theiler's murine encephalomyelitis virus (TMEV) infection, a mouse model of multiple sclerosis. However, the precise mechanism by which this occurs remains unknown. The present study suggests that SDR exacerbates TMEV disease course by priming virus-induced neuroinflammation. It was demonstrated that IL-1β mRNA expression increases following acute SDR; however, IL-6 mRNA expression, but not IL-1β, is upregulated in response to chronic SDR. Furthermore, this study demonstrated SDR prior to infection increases infection related central IL-6 and IL-1β mRNA expression, and administration of IL-6 neutralizing antibody during SDR reverses this increase in neuroinflammation.

Alterations in anxiety-like behavior following knockout of the uncoupling protein 2 ( ucp2) gene in mice

Aims Uncoupling protein 2 (UCP2) is a mitochondrial protein that reduces oxidative stress and has a protective function in chronic inflammatory diseases such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. UCP2 is strongly expressed in areas implicated in the central regulation of stress and anxiety. Therefore, we compared the neuroendocrine regulation of stress responses, immunity and behavior in UCP2-deficient and wildtype C57BL/6J mice under psychological stress. Main methods Stress was induced by social disruption (SDR) and anxiety-like behavior was examined using the elevated plus-maze (EPM). Serum corticosterone was determined by radioimmunoassay and brain neurotransmitter concentrations were analyzed by HPLC of whole brain homogenates. T cell activation and tumor necrosis factor (TNF)-α production of mitogen-activated splenocytes were determined in vitro by flow cytometry staining of CD25, CD69 and CD71 on CD4 cells, and ELISA, respectively. The influence of corticosterone on UCP2 expression of splenocytes was analyzed by Western blot. Key findings At baseline, UCP2-deficient mice were significantly more anxious in the EPM than wildtype mice, and this phenotype was exacerbated after SDR stress. The corticosterone response after SDR + EPM was reduced in UCP2-deficient mice compared to wildtype mice. Corticosterone in turn downregulates UCP2 expression in splenocyte cultures of wildtype mice at physiological concentrations. Dopaminergic and serotonergic turnovers were increased in UCP2-deficient mice after SDR + EPM. While T-helper cell activation-marker expression was reduced, TNF-α production was increased in UCP2-deficient mice after SDR + EPM. Significance Our study shows that UCP2 is involved in anxiety-like behavior and modulates neuroendocrine and immune responses after stress.

Immunogenic dendritic cells primed by social defeat enhance adaptive immunity to influenza A virus

Dendritic cells (DCs) sample their surrounding microenvironment and consequently send immunogenic or regulatory signals to T cells during DC/T cell interactions, shaping the primary adaptive immune response to infection. The microenvironment resulting from repeated social defeat increases DC co-stimulatory molecule expression and primes DCs for enhanced cytokine responses in vitro. In this study, we show that social disruption stress (SDR) results in the generation of immunogenic DCs, capable of conferring enhanced adaptive immunity to influenza A/PR/8/34 infection. Mice infected with influenza A/PR/8/34 virus 24 h after the adoptive transfer of DCs from SDR mice had significantly increased numbers of D bNP 366-74CD8 + T cells, increased IFN-γ and IFN-α mRNA, and decreased influenza M1 mRNA expression in the lung during the peak primary response (9 days post-infection), compared to mice that received DCs from naïve mice. These data demonstrate that repeated social defeat is a significant environmental influence on immunogenic DC activation and function.

Abstract 3270: Environmental stress results in an earlier onset of tumors in a HER2/Neu breast cancer model

Abstract Introduction Possible environmental effects on the development of HER2+ breast cancer have received relatively little research attention. Here we used the well-established MMTV-neu mouse model, which overexpresses mammary ErbB2 (HER2-neu) and stochastically develops primary tumors over 6-12 months, to test the hypothesis that chronic exposure to environmental stressors may result in an earlier onset of tumors. Experimental Procedures Female mice (FVB/N-Tg(MMTVneu)202Mul/J) were purchased from Jackson Labs at age 4-5 weeks, housed in standard cages in an isolation chamber in a controlled-access animal room, and randomly assigned to one of four experimental exposure conditions in a factorial design that was maintained for the course of the study: 1) Restraint stress (RS) 90 min - 1x/wk (n=24); 2) Social disruption stress (SD) (via cage mate switching across home cages) 2x/wk (n=23); 3) RS&SD (n=22); 4) home cage control (HC)(n=20). Mice were visually inspected and palpated for tumor development 1x/wk (blinded as to treatment group). All mammary glands from each mouse were processed for histologic evaluation one week following positive tumor palpation. All palpated tumors were histologically confirmed by a pathologist's evaluation of H&E sections (blinded as to treatment group). Results Consistent with the study hypothesis, the results indicated that mice chronically exposed to the two environmental stressors (RS&SD) developed primary tumors at a significantly (p<0.002, Cox regression) younger age (mean +/− se: 29.8 +/− 0.7 wk) than the controls (HC) (34.4 +/− 0.8 wk). The mice chronically exposed to just one of the stressors developed tumors at an intermediate age (RS = 32.0 +/− 0.8; SD = 32.3 +/− 0.8 wk), suggesting a possible additive pattern of stress responses. Consistent with stress effects early in the process of tumorigenesis, evidence of mammary hyperplasia in the H&E sections was also significantly (p<0.04) more frequent in mice exposed to both stressors (RS&SD) compared with the control group (HC). Body weights increased significantly over the entire course of the study and did not differ across groups, suggesting that the group differences in tumor development were not due to a failure to thrive. Conclusions Exposure to environmental stressors may speed the development of tumors in this transgenic model of HER2+ breast cancer. These novel findings suggest the importance of further investigation to determine the mechanisms responsible for these effects of exposure to environmental stressors. (Support: CA120795) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3270.

Molecular mechanisms of stress-induced glucocorticoid resistance in splenic macrophages: A role for p38 MAPK (98.22)

Abstract Stress has been shown to increase production of glucocorticoids (GC’s), which suppress the inflammatory response. However, the increased levels of circulating GC’s observed following social disruption stress (SDR) fail to suppress cytokine production or induce apoptosis in splenic CD11b+ cells from WT mice, suggesting that these cells are GC resistant. Moreover, CD11b+ cells from IL-1R1 knockout (KO) mice are not GC resistant following SDR. The results of the present study show that following LPS and corticosterone (LPS/cort) stimulation, CD11b+ cells from WT SDR mice displayed an increase in cytoplasmic p38 phosphorylation (p-p38) when compared to controls. The increase in p-p38 was associated with an increase in nuclear translocation of the GC receptor phosphorylated at Ser234 (GR-pS234), within SDR mice compared to controls. Studies conducted with p38 and JNK inhibitors revealed that a reduction in p38 activity led to an increase in JNK activation and that cytoplasmic GR-pS234 was maintained in SDR and control mice. Furthermore, p-p38 was notably absent in KO macrophages from SDR and control mice stimulated with LPS/cort. These data confirm that SDR enhances GR-pS234 and JNK may facilitate this phosphorylation in the absence of p-p38. These data also support a role for p38 in induction of GC resistance.

Influenza Virus-Specific Immunological Memory Is Enhanced by Repeated Social Defeat

Immunological memory (MEM) development is affected by stress-induced neuroendocrine mediators. Current knowledge about how a behavioral interaction, such as social defeat, alters the development of adaptive immunity, and MEM is incomplete. In this study, the experience of social disruption stress (SDR) prior to a primary influenza viral infection enhanced the frequency and function of the T cell memory pool. Socially stressed mice had a significantly enlarged population of CD8(+) T cells specific for the immunodominant NP366-74 epitope of A/PR/8/34 virus in lung and spleen tissues at 6-12 wk after primary infection (resting memory). Moreover, during resting memory, SDR-MEM mice responded with an enhanced footpad delayed-type hypersensitivity response, and more IFN-gamma-producing CD4(+) T cells were detected after ex vivo stimulation. When mice were rechallenged with A/PR/8/34 virus, SDR-MEM mice terminated viral gene expression significantly earlier than MEM mice and generated a greater D(b)NP(366-74)CD8(+) T cell response in the lung parenchyma and airways. This enhancement was specific to the T cell response. SDR-MEM mice had significantly attenuated anti-influenza IgG titers during resting memory. Similar experiments in which mice were primed with X-31 influenza and challenged with A/PR/8/34 virus elicited similar enhancements in the splenic and lung airway D(b)NP(366-74)CD8(+) T cell populations in SDR-MEM mice. This study demonstrates that the experience of repeated social defeat prior to a primary viral infection significantly enhances virus-specific memory via augmentation of memory T cell populations and suggests that social stressors should be carefully considered in the design and analysis of future studies on antiviral immunity.

Repeated social stress enhances the innate immune response to a primary HSV-1 infection in the cornea and trigeminal ganglia of Balb/c mice

Three to 5 days after a primary HSV-1 infection, macrophages infiltrate into the trigeminal ganglia (TG) and produce anti-viral cytokines to reduce viral replication. Previous research demonstrated that social disruption stress (SDR) enhances the trafficking of monocytes/macrophages from the bone marrow to the spleen and increases pro-inflammatory cytokine production in vitro and in vivo. The impact of SDR on the trafficking of these cells to loci of herpes simplex virus type 1 (HSV-1) infection and subsequent function has not been examined. The following studies were designed to determine whether SDR would enhance the innate immune response during a primary HSV-1 infection by increasing the number of macrophages in the cornea and TG, thus increasing anti-viral cytokine production and reducing viral replication. BALB/c mice were exposed to six cycles of SDR prior to ocular infection with HSV-1 McKrae virus. Flow cytometric analysis of cells from the TG revealed an increase in the percentage of CD11b+ macrophages in SDR mice compared to controls. Immune cell infiltration into the cornea, however, could not be determined due to low cell numbers. Although gene expression of IFN-β was decreased, SDR increased gene expression of IFN-α, and TNF-α, in the cornea and TG. Examination of viral proteins showed decreased expression of infected cell protein 0 (ICP0), glycoprotein B (gB), glycoprotein H (gH) and latency-associated transcript (LAT) in the TG, however, expression of ICP0 and gB were elevated in the cornea of SDR mice. These results indicate that the innate immune response to HSV-1 was altered and enhanced by the experience of repeated social defeat.

127. Chronic social disruption stress facilitates zymosan-induced mechanical allodynia

127. Chronic social disruption stress facilitates zymosan-induced mechanical allodynia

Social Stress Enhances Allergen-Induced Airway Inflammation in Mice and Inhibits Corticosteroid Responsiveness of Cytokine Production

Chronic psychosocial stress exacerbates asthma, but the underlying mechanisms remain poorly understood. We hypothesized that psychosocial stress aggravates allergic airway inflammation by altering innate immune cell function. The effects of stress on airway inflammation, lung function, and glucocorticoid responsiveness were studied in a novel in vivo murine model of combined social disruption stress and allergic sensitization. The effects of corticosterone were assessed on cytokine profile and glucocorticoid receptor activation in LPS-stimulated spleen cell cultures in vitro. Airway inflammation resolved 48 h after a single allergen provocation in sensitized control mice, but not in animals that were repeatedly exposed to stress before allergen challenge. The enhanced eosinophilic airway inflammation 48 h after allergen challenge in these mice was associated with increased levels of IL-5, GM-CSF, IgG1, thymus-activated and regulatory chemokine, TNF-alpha, and IL-6 in the airways and a diminished inhibition of these mediators by corticosterone in LPS-stimulated splenocyte cultures in vitro. Stress-induced reduction of the corticosteroid effects paralleled increased p65 expression and a decreased DNA-binding capability of the glucocorticoid receptor in vitro. Furthermore, glucocorticoid receptor mRNA and protein expression in the lungs of mice exposed to both stress and allergen was markedly reduced in comparison with that in either condition alone or in naive mice. Thus, exposure to repeated social stress before allergen inhalation enhances and prolongs airway inflammation and alters corticosterone responsiveness. We speculate that these effects were mediated at least in part by impaired glucocorticoid receptor expression and function.

Mechanisms of social disruption stress induced glucocorticoid resistance (91.16)

Abstract Social disruption (SDR) stress increases splenic CD11b+ myeloid cells, which produce high levels of proinflammatory cytokines upon Toll-like receptor ligation and show impaired nuclear translocation of the GC receptor (GCr) after corticosterone (cort) stimulation. To uncover the mechanism of GC resistance, p38 MAPK (p38) expression and phosphorylation were investigated along with phosphorylation of the GCr. To examine the mechanism(s) of enhanced proinflammatory cytokine responses, CD11b+ splenocytes from control (HCC) and SDR mice were stimulated with lipopolysaccharide in the presence of cort. SDR and HCC CD11b+ cells show similar levels of unphosphorylated p38 protein. CD11b+ cells from SDR mice exhibited an increase in phosphorylation of p38 and of the GCr. Since phosphorylation of p38 has been linked to GCr phosphorylation in humans, it is likely that a same phenomenon occurs here, though it must be confirmed. Since, phosphorylation of the GCr reduces steroid-induced cytokine repression; this may explain the enhanced cytokine expression. These data show that phosphorylated forms of p38 and GCr play a role in GC resistance. Support: NIH grants NIMH/RO1MH046801-16 and NIDCR/T32DE014320-6